Larry Sandler: Personal Recollections

FOR many years Laurence Sandler (1929–1987) was my closest scientific colleague. He died suddenly and unexpectedly 12 years ago at the age of only 57. Larry was an original, and no tribute to him can be complete without anecdotes, some of which I will relate. During the previous three decades he had been among the leading Drosophila geneticists and perhaps the leading contributor of students; their impact on the field in the succeeding years continues to be immense. Larry was born and raised in Brooklyn, and he often told stories of those days, many probably apocryphal. Despite being a city boy, from an early age he had an interest in agriculture, especially chickens. He claimed to have had a job during high school painting manure on cold-storage eggs so that they could be sold as farm fresh. He subsequently attended farm school in Farmingdale, Long Island; he described his failure in wall building–his wall fell over while being examined by the instructor–as motivating his decision to transfer to Cornell. He spoke fondly of his years at Cornell, where he discovered genetics and where he was able to attend courses in many disciplines taught by excellent professors; he became wedded to the academic life. I first met Larry in 1952 while I was en route from Pasadena to my postdoctoral fellowship with Kenneth Cooper at Princeton University. I stopped in Columbia, Missouri, to visit Ed Novitski; he had been my ex officio mentor both when I was a master's degree student while Ed was a postdoctoral fellow at the University of Missouri and during my doctoral studies at Cal Tech, where Ed was a research fellow before he returned to the University of Missouri for a faculty position. Larry had recently arrived at Missouri from Cornell. He had hoped to study chicken genetics at Northern Illinois University in Dekalb; however, since no support was available in chicken labs, Adrian Srb advised him to accept an interim slot with Novitski. That summer I didn't see much of Larry because he was working in the corn fields for L. J. Stadler. During the two decades prior to that time, the University of Missouri had become an outstanding center for research in plant genetics under the aegis of Stadler (see Roman 1988). A year later I joined the Novitski laboratory for a second postdoctoral year. By that time Larry was Ed's pride and joy; he had absorbed Drosophila lore like a sponge, and all thoughts of chicken genetics had vanished. He and Gerry Braver had just submitted their paper on meiotic loss of unpaired chromosomes. At the same time Larry and Novitski were exploring the population consequences of nonrandom disjunction, which Novitski had described previously. They originated the seminal concept of meiotic drive as a force for changing allele frequencies in natural populations (Sandler and Novitski 1957). At the same time Larry was also investigating the origin of certain compound X chromosomes via reversed sister-chromatid exchange. During that year, he and I used adjacent microscopes and embarked on our first collaboration, on the meiotic behavior of small free-X duplications. It was after winter break of 1953–1954 that Larry returned from Brooklyn with his new bride, Iris; she immediately joined Novitski's lab as a graduate student. Years later, when introducing Larry to a seminar audience in Eugene, Ed enthused about the most promising graduate student that he had supervised and how it was his great pleasure to introduce her husband–the day's speaker. In the summer of 1954, I moved to a position in the Biology Division of the Oak Ridge National Laboratory, but Larry and I continued our collaboration on the free duplications. Two years later, both Ed and Larry moved to Oak Ridge: Larry on a postdoctoral fellowship and Ed to head the Drosophila group, a position vacated a year earlier by Bill Baker, who had moved to the University of Chicago to occupy the slot freed by the retirement of Sewall Wright. At Oak Ridge, Larry and I completed our work on the duplications and sperm dysfunction. We found that some free-X duplications were transmitted at very low frequencies by males, but we could find no gametes from which they had been lost nor any appreciable zygote mortality; they had to have been lost sometime between meiosis and fertilization. We then embarked on a second project, that of applying Muller's doubler chromosome technique to the construction of the six possible configurations of compound X chromosomes, all marked with heterozygous markers for the eventual use in tetrad analysis. During that period we continued the practice, initiated in Novitski's lab in Missouri, of rigging the wall clock to run backward; it was confusing to anyone who did not work in the lab, but we had learned to read the mirror-image time without difficulty. Mary Lou Pardue, who was making cytological preparations in the lab at the time, says that today she sometimes gets confused about the direction that the minute hand is moving when she's timing staining procedures. At the end of 1957, Novitski moved on to a faculty position at the University of Oregon, and I tried to convince Larry to remain in Oak Ridge. His heart, however, was set on returning to academia, and he had decided on Jim Crow's lab at the University of Wisconsin. Upon arrival he became fascinated by a chromosome that was preferentially recovered from males relative to its homologue, which had been isolated from a natural population in Madison by a first-year graduate student, Yuichiro Hiraizumi. It seemed to be a genuine case of meiotic drive acting in a natural population. This was Segregation Distorter (SD). Studies of SD led to the publication of eight substantial papers by Sandler and Hiraizumi over the next two years, and the phenomenon of segregation distortion was to occupy Larry off and on for the remainder of his career. The history of SD is summarized in a Perspectives article (Crow 1988), and a symposium on meiotic drive initiated by, and dedicated to the memory of, Larry appeared in the American Naturalist (Temin et al. 1991). Larry had the habit of pacing back and forth while thinking; in Wisconsin, a long narrow office was planned to facilitate this predilection. At Madison, his interactions with James Crow and Sewall Wright introduced him to the disciplines of population genetics and evolution; this exposure prepared him to teach courses in those subjects in later years. What turned out to be the first annual Drosophila Research Conference was held in Madison, Wisconsin in the fall of 1958. Larry, Bill Baker, Jim Crow, and I each presented our work for several hours. Ted Pittenger, a Neurospora geneticist from Marquette University, also discussed his work. Of course, other members of Crow's laboratory also attended and participated in the sessions; among them were Yuichiro Hiraizumi, Rayla Temin (then Greenberg), Elaine Mange (then Johansen), and Tom Gregg. R. A. Brink talked about his then current work with maize. What started out as an informal get-together of a handful of individuals to talk about flies has developed into an internationally attended yearly meeting that draws up to 1500 participants. After two years as a postdoctoral fellow and two years as an Assistant Professor at the University of Wisconsin, where his course in cytogenetics was very popular, Larry was recruited by Herschel Roman to the Genetics Department at the University of Washington in 1961. The Sandlers' two children, Jack and Dianna (Dee), were born in Madison. Several of Larry's colleagues recount that when they invited him to join the Genetics Department at the University of Washington, they had the idea that he could provide students with some historical perspectives and instruction in classical genetics; the consensus at the time was that Drosophila genetics was passé and that he would probably not be active in supervising graduate students. They were in for a big surprise. Even though he never embraced molecular genetics, the students flocked to him, and he provided the field with a prestigious cadre of Drosophila researchers, including John Merriam, Leonard Robbins, Bruce Baker, Adelaide Carpenter, Jeff Hall, Barry Ganetzky, Scott Hawley, Ian Duncan, Joe O'Tousa, Paul Szauter, Larry Goldstein, Jim Mason, Kent Golic, and Bill Sullivan. Jon Tomkiel and Glenn Yasuda were both Ph.D. students in Larry's lab at the time of his death. They finished in other fly labs (Jon with Barbara Wakimoto and Glenn with Gerold Schubiger). Several investigators who spent sabbatical years with Larry are Arthur Mange, John Sved, Terry Lyttle, and Sergio Pimpinelli. Larry was preparing to spend a period in Sergio's lab in Bari, Italy, at the time of his death. Larry was a dedicated teacher, both to large classes of undergraduates and to smaller groups of graduate students. To undergraduates he was both entertaining and popular; he was rigorous, but he never let his desire to cover the subject get in the way of a good story. He was also very effective one on one and in small groups. The accompanying photograph catches him in the act. Larry was especially conscientious about teaching graduate students, and many of the graduate students in the department were greatly influenced by his teaching. He was fond of Socratic interactions with his students; he gathered them together weekly, and they would go over research papers in minute detail, examining experimental rationales, results, and conclusions in a question-and-answer format. He was pleased when the more senior graduate students instructed the new ones. He consciously weaned his students from his input over the course of their graduate careers, so that in their final year of thesis preparation they were essentially independent. Each student had an exclusive research project, and theses were invariably published as single-author articles, with Larry mentioned in the acknowledgments. The thrust of the experimental work in his laboratory was the investigation of the behavior of chromosomes during meiosis as elucidated through designed crosses and rigorous genetic analysis. Larry was unconcerned with the need to tackle popular topics; if the data posed an interesting question, that was incentive enough for him to accept the challenge. His approach was that of a scholar rather than that of someone whose main concern was catering to the current interests of the granting agencies; nevertheless, he never lacked for support. Laurence Sandler in 1984. Photo by Kent Golic. In the summer of 1965, I drove with my family from Oak Ridge to Seattle to attempt with Larry the construction of a tandem compound ring X chromosome: two X chromosomes in the same sequence attached end-to-end and conjoined into a ring configuration. It was the last of six different heterozygously marked compound X chromosomes that remained for us to produce. Novitski had previously made and analyzed the progeny of all six, but without the advantage of heterozygous markers. We succeeded in making the tandem ring, and over the next four years he and I completed the tetrad analysis of three different tandem compound X chromosomes. During that summer Ed invited us down to Eugene to write a contribution to a volume on genetic techniques, being edited by Walter Burdette, about the use of compound-generating Bar-Stone duplications. At the end of that summer Larry attended the Eleventh International Congress of Genetics in Bellagio, Italy. In the process he spent some time in Rome. He decided to take a stroll around the city; he wrote down the name of his hotel, Albergo, in case he got lost, so he could have a taxi return him. Fortunately he found the hotel by himself because, as he learned later, “albergo” simply means “hotel.” That visit to Rome convinced him of his desire to learn Italian and to return. He and Iris immediately began to study Italian, in which they became remarkably fluent. Years later, in preparation for a sojourn in Israel, Larry tackled Hebrew with the same ferocity as he had Italian. He insisted on speaking the local language when he was in those countries. Larry and I decided to try to do a sabbatical year together in Rome. We met in his father's apartment in Brooklyn and spent several days assembling a proposal to screen natural populations for recessive mutations affecting meiosis. It was an early attempt to apply the mutational approach, so successful in the dissection of metabolic pathways in microorganisms, to the study of a biological process in a higher eukaryote and to investigate what Charles Langley has termed the genetics of genetics. Luckily we were both funded, and we arrived en famille at the Institute of Genetics at the University of Rome, headed by Professor Giuseppe Montalente. We occupied adjacent apartments on the eighth floor of a building about four blocks from the institute. I had taken delivery of a new Volkswagen microbus in Paris, and we and the Sandlers explored central Italy together on many weekends. We joined forces in Rome with Benedetto Nicoletti and a student, Gianni Trippa, and began to collect flies, first in the fruit market and later, at the time of the vendemmia, in the wineries on the outskirts of Rome. Our first foray into the central fruit market provided the basis of one of Larry's oft-told anecdotes. Because of his ineptitude with an insect net and his command of Italian, which was nearly perfect, it was my job to sweep for flies and his to explain my antics to the astonished onlookers. He explained that I was mentally unbalanced but harmless and that, in any case, he was there to make sure that I didn't get out of hand. Our genetic approach was to generate flies that carried marked X's and 4's and were homozygous for both chromosomes 2 and 3 derived from natural populations; the progeny of these flies were then scored for X chromosome recombination and X and 4 disjunction. We recovered half a dozen mutations that served as thesis material for Larry's students in subsequent years. By confining our analysis to genomes in which both the second and third chromosomes were lethal free, we surely missed interesting meiotic mutants in lines in which one carried a other mutants recovered were the only SD chromosome available at the time, and a A good of Larry's in the two decades was dedicated to the of Because our meiotic was so successful and Larry and I decided to on the of The was to the large with a of and by of with to generate duplications and At the of the summer of the in my laboratory and drove in four one of which carried my to Seattle to join forces with the members of Larry's lab Baker, Adelaide Carpenter, and Jeff to a large of By the time we arrived in the X had been and the crosses had been of us then began to the for of the chromosome markers and with the We scored some and recovered over This of the was completed by the end of We then began the of the by chromosome analysis. Of course, these were not completed by the end of the summer and had to be continued into the fall and I finished the back in while Bruce and Adelaide finished the in the end of the fall we were to make crosses between attached males one to attached X an adjacent We to down the chromosomes, as available would at of and of the all of these crosses began to the Sandler lab to for the winter We a student together with and we began to the of these nearly We were to find that the of the in as did about half of the the that the two an one led us to that the of heterozygous were with rather than to of a We time off on to have a on the but we had to take the up to the on the because Larry to set on the he a and a In Iris Sandler a Ph.D. in the history of she was so at the that she didn't that it was Larry who During the Larry and Iris explored the biological of the last to of that time were to the work of The Sandlers were to into the history of genetics at the time that Larry Of course, Larry the of and and on study In the early years he was with so to attend study he from Seattle to Washington, by he claimed that it him several days to Larry served as of of Genetics for years, from its the time of his death. He also served as of Genetics and on the of of the Genetics of in the he initiated the of the first Drosophila genetics meeting in with the International Congress of held in in In the fly were being by different groups of that year the meeting in was by the Seattle of that year was the of Larry the of some he that a an could to his In to this to the local he was in the of the annual fly meeting and its to the Genetics of He was in his He the same route to and from the at the same time He claimed that, were he to from this he would get He had his for the who the At his had its on the His graduate students him by painting of the of his and The same of could be on the in his at had its position. they were Larry would return them to their position the He had a in his he turned it to the next day's and two 2 for the next day's use just before at He without any attempt by his students to him by of these I a from Kent was over my data one and that I had only one it was to on days and I told him that it was not Larry that I was only to do one because I had not a after the that made up the Larry he wrote the immediately because he that he would return for the next he an to his he was in its This off in his of Italian and The only in which he was was to the I he had the for he could a with his it out of Larry himself an of and I his at the of by the then during the He was about his many years he he much was fond of and he a he became and and he had to up At some in the Larry was he became about his and he his He started and began in the at he did not go to the on but in to to his he made an to that He lost a and his It was a His colleagues in Seattle to Larry as a I that the most of that he by himself was a He never on his through a compound he with Novitski the that could be learned from that could not be from He did have and an designed for Ed as I can make it was never in Seattle by who has it in He in as a he would in to in his while more was to by Larry appeared one a lab and that it just like the lab that his J. used to Larry that it was in that very same lab and that he had it on but two in Missouri and this time in what the Larry that in both he had the of his Larry was a He and Iris would visit the and return with a large of to be read over the next He was a great and had a of from his many of which I They were also the of their are with was no more on the and at the time of Larry's they were embarked on the the second floor has not under the I that Iris is Larry read Italian and Hebrew as as and He made to Italian and to an Italian His was by the Drosophila to his memory is the Sandler in with Larry's to graduate is for the Ph.D. thesis on Drosophila of the previous academic year. The a on the of the annual Drosophila Research The Genetics Department of the University of Washington also an annual Sandler I to those who have made and for this They Adelaide Carpenter, Larry Goldstein, Kent Golic, Scott Hawley, most Iris