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Phage Integration and Chromosome Structure. a Personal History ANRV329-GE41-01 ARI 2 November 2007 12:22 by Annual Reviews on 12/13/07. For personal use only. Annu. Rev. Genet. 2007.41:1-11. Downloaded from arjournals.annualreviews.org ANRV329-GE41-01 ARI 2 November 2007 12:22 Phage Integration and Chromosome Structure. A Personal History Allan Campbell Department of Biological Sciences, Stanford University, Stanford, California 94305-5020; email: [email protected] Annu. Rev. Genet. 2007. 41:1–11 Key Words First published online as a Review in Advance on lysogeny, transduction, conditional lethals, deletion mapping April 27, 2007 Abstract by Annual Reviews on 12/13/07. For personal use only. The Annual Review of Genetics is online at http://genet.annualreviews.org In 1962, I proposed a model for integration of λ prophage into the This article’s doi: bacterial chromosome. The model postulated two steps (i ) circular- 10.1146/annurev.genet.41.110306.130240 ization of the linear DNA molecule that had been injected into the Annu. Rev. Genet. 2007.41:1-11. Downloaded from arjournals.annualreviews.org Copyright c 2007 by Annual Reviews. cell from the phage particle; (ii ) reciprocal recombination between All rights reserved phage and bacterial DNA at specific sites on both partners. This 0066-4197/07/1201-0001$20.00 resulted in a cyclic permutation of gene order going from phage to prophage. This contrasted with integration models current at the time, which postulated that the prophage was not inserted into the continuity of the chromosome but rather laterally attached or synapsed with it. This chapter summarizes some of the steps leading up to the model including especially the genetic characterization of specialized transducing phages (λgal ) by recombinational rescue of conditionally lethal mutations. The serendipitous discovery of the conditional lethals is also described. 1 ANRV329-GE41-01 ARI 2 November 2007 12:22 PRELUDE what I was getting into. I had no special incli- This chapter covers part of my career around nation for research. I liked learning and en- joyed being a student and taking classes. I’ve gal: a cluster of 1960 and the questions that occupied my at- genes whose tention at that time. A brief summary of my read many accounts from scientists (including products are needed previous life indicates where I was coming some of my friends) who were motivated by to metabolize the from. At the end, I’ll say something about the ambition for research success from an early sugar galactose subsequent 40 years. age. Others of us just stumbled into research In high school I was inclined toward cre- careers. ative writing, but I thought a career in science My favorite professors at Berkeley had all should provide more secure employment. It been research-oriented, but that was not what was a fortunate decision, because I realized in had drawn me to them. I cared very little about retrospect that I have virtually no talent for how much they had accomplished. What I effective original writing. My best subject in liked was that they seemed to have thought school was mathematics. As a potential scien- deeply about the basic issues in their fields. It tist, I suffered from an inability to do much took me much longer to appreciate fully the of anything right in the laboratory. But I also linkage between depth of understanding and felt that experimental science kept me in touch hands-on involvement in research. with reality, whereas mathematics invited me In Urbana the Spiegelman lab was next to to dwell within a dream world of abstractions. the Luria lab. Salva’s interests were turning So in 1946 I enrolled as a chemistry major toward temperate phages, and Joe Bertani, at the University of California. My basic atti- then a research associate in Salva’s lab, was tudes toward scientific thinking were strongly performing many of the pioneering experi- shaped by the Berkeley chemists. Probably ments on lysogeny. I finished my thesis with my favorite professor was William Giauque, Sol in 1953, then started my first academic ap- who won a Nobel Prize for low temperature pointment as Instructor in Bacteriology at the chemistry during my senior year. I had never University of Michigan Medical School (an encountered anyone so completely immersed appointment interrupted almost immediately in science. He seemed a worthy role model by two years of military service). At Michigan, (and not because of his Nobel). Outside of I started out working on yeast (a continua- the Chemistry Department, my imagination tion of my doctoral research), but spent the was stimulated by the biochemically oriented summer of 1956 with Joe Bertani in Pasadena by Annual Reviews on 12/13/07. For personal use only. microbiologists—especially Mike Doudoroff (where he had moved to the Cal Tech phage and Roger Stanier. Inspired by them, I de- group). I arrived with a plan for some ex- cided in my senior year to apply to grad- periments on restriction/modification (which uate school in microbiology. Roger recom- produced some very preliminary results), but Annu. Rev. Genet. 2007.41:1-11. Downloaded from arjournals.annualreviews.org mended several places, and also directed then became engrossed with specialized trans- me toward C.B. van Niel’s course at the duction of the gal operon by phage λ. Hopkins Marine Station that summer (1950). van Niel became a second role model. I then became a graduate student of Sol Spiegelman’s SPECIALIZED TRANSDUCTION at the University of Illinois. Before I arrived, At that time, Jean Weigle had joined the Cal I.C. Gunsalus and Salva Luria had been re- Tech phage group, but spent his summers cruited to Illinois, which then arguably had in Geneva (where he held a professorship the best bacteriology department in the world in physics). When I arrived in Pasadena for (at least for basic, nonmedical bacteriology.) the summer, he had left behind some pre- Graduate school application was much less liminary notes that Joe thought I might fol- organized than now, and I had little idea of low up on. Specialized transduction had been 2 Campbell ANRV329-GE41-01 ARI 2 November 2007 12:22 discovered by Larry Morse (16), but Jean tle fiefdoms. The tradition of arts colleges wanted to look into it further (19). I was un- comes from clerical institutions, which of aware at the time that he had also encouraged course had their own discipline but adapted SOS mutagenesis: Werner Arber in Geneva to investigate the more readily to a democratic structure. induction of same system. Eventually, Werner and I came, I was not offered any position in arts mutations by action quite independently, to very similar conclu- colleges at that time, but Miloslav De- of the products of sions. Two such parallel studies are about the merec, Director of the Carnegie Institu- some of the bacterial right number to provide corroboration but tion Department of Genetics at Cold Spring genes inducible by DNA damage avoid needless duplication. Harbor, wanted a one-year appointment to On returning to Michigan, I postponed replace George Streisinger, who was spend- further work on yeast (for 50 years now) and ing the year abroad. Cold Spring Harbor dedicated myself full time to the study of spe- was a marvelous place to do research, cialized transduction. I had a small NIH grant free from other obligations, and the senior to support the yeast work, so I informed NIH people—Demerec, Barbara McClintock and in my annual renewal that I was now work- Al Hershey—provided inspiration and moral ing mainly on phage. I am eternally grateful support. to have started my career at a time when such The initial task I set myself that year was flexibility was routine. to find out more precisely which segment of My initial work, paralleled by that of Arber the λ genome was missing from λgal. I knew (3), examined the effect of multiplicity of that the h gene was gone and that some other infection on the frequency and nature of genes were present. Dale Kaiser had made a the transductants (5)—something that nei- good map of λ, but the number of available ther Morse nor Weigle had done. The re- genetic markers was very limited. So I decided sults indicated that transduction was carried to make more. out by chimeric phages that had lost some of Jean Weigle had discovered that, if both their own genes while acquiring the nearby λ and Escherichia coli are exposed separately gal genes. The phage DNA that was miss- to UV light and then the λ is plated on the ing included the h gene, which was in the irradiated host, a substantial fraction of the middle of the phage genetic map. The find- observed plaques are mutant. The mecha- ing heightened my consciousness that most nism was unknown. One favored hypothesis previous students of lysogeny had treated the at the time was recombinational rescue from by Annual Reviews on 12/13/07. For personal use only. prophage as an indivisible unit (analogous to a postulated prophage homolog in the host, the concept of the gene that prevailed in the but it is now understood as inducible SOS first half of the twentieth century), whereas it mutagenesis arising during radiochemical re- might sometimes be more relevant to try trac- pair (9). My intention was to collect small Annu. Rev. Genet. 2007.41:1-11. Downloaded from arjournals.annualreviews.org ing the origins of the individual genes of the plaque mutants, map them by phage crosses, prophage. then see whether their wild-type alleles could Two years in the Michigan Medical School be rescued from λgal.
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