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October 1957 Changed the Course of American Science and of My Own Getting Along with a Little Help from My Friends The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Fink, Gerald R. “Getting Along with a Little Help from My Friends.” Journal of Biological Chemistry 284.36 (2009): 23885-23890. As Published http://dx.doi.org/10.1074/jbc.X109.029389 Publisher American Society for Biochemistry and Molecular Biology, Inc. Version Original manuscript Citable link http://hdl.handle.net/1721.1/56011 Terms of Use Attribution-Noncommercial-Share Alike 3.0 Unported Detailed Terms http://creativecommons.org/licenses/by-nc-sa/3.0/ Getting Along With a Little Help sparked my interest in metabolism and From My Friends supported my growing awareness that there was a lot going on outside of our town. Yamins took an interest in my education and Gerald R. Fink channeled me towards his alma mater, Whitehead Institute/MIT Amherst College. A friend from high school, Harold Varmus, then a freshman at The successful launching of the Russian the college, encouraged me to come and satellite, Sputnik, in October 1957 changed avoid becoming "…just another grind in the course of American Science and my Harvard Yard." future. The shock waves reached my high school in Freeport, N. Y., a complacent College-a first taste of the regulation suburb on the south shore of Long Island problem notable for its easy access to New York City and Jones Beach State Park. The school was In my junior year at Amherst two lectures uninspiring---its heroes were the athletes weighed heavily as I thought about my and cheerleaders, who were objects of future. One was by Linus Pauling from admiration and respect especially by those Caltech, who was a guest speaker in the outside their circle. physical chemistry class. Pauling peppered his explanation of the ideal gas laws with Fear gripped the nation. We had been told anecdotes about his youthful interest in we were winning the missile race, but the measurement as he watched his father work glittering new star in the evening sky in the pharmacy. He bobbed up and down blinked undeniable evidence that we were excitedly, punctuating sentences with a behind. Something had to be done. broad smile, and weaving his personal Overnight, science became a national observations together with the science in a priority. Our principal, a former high school way that made everything seem vital and athletic star, grasping for familiarity, clear. Making the difficult so simple and announced to the school that the Russians entertaining was alluring. had launched something the size of a basketball. Local engineers from Grumann Another influence was a lecture by Professor and Republic Aviation took the challenge Benjamin DeMott, who taught a course on more seriously and, energized by the the 19th century continental novel. DeMott national dread of Soviet technological often asked one of us to read the class a superiority, taught advanced math courses passage from the novel under study so that pro bono at our school. One even switched we could feel the power of the words. On jobs and became a teacher at the high prom weekend DeMott himself read the school. Overnight, the cheerleaders took an Grand Inquisitor scene from The Brothers interest in the smart kids. Karamazov. The bell rang signaling the end of class, but stunned by the drama of his A family friend, Jacob Yamins, perhaps the performance, no one rose. Slowly, one, then only Bohemian in town, noticed my growing another of the couples released from his interest in science and invited me to visit his spell, ambled silently out of the room. laboratory at National Dairy. An organic chemist trained at MIT, Yamins was These experiences confounded my decision- working on a test for phenylketonuria and --should it be science or literature? I am not the synthesis of L-DOPA on which he certain what pushed me towards science, but pinned his hopes for a cure for Parkinson's my impending marriage at the end of my disease. His stories about similar studies in junior year and the award of an NSF laboratories working on the same problems summer fellowship to start a research project in Baltimore, St. Louis, and Berkeley on Drosophila in the laboratory of Dr. Philip Although a number of histidine genes were Ives, probably played a big role. located on different chromosomes, some of these loci might encode more than one The Amherst/NSF research program protein and be suitable candidates for an extended into my senior year and included a operon. The first step in determining gene student seminar program. My assignment organization would require associating each was to present the now classic JMB paper by of the known histidine mutants with its Jacob and Monod (1) on the operon model enzymatic defect. As a novice, I had failed for the regulation of metabolism. The to appreciate that the substrates for the omniscience of the paper mesmerized me; it requisite assays were not commercially seemed to explain everything from the available. My enthusiasm was replaced by regulation of bacterial physiology to animal the discouraging reality that I would be development. I bought into a comment bogged down in synthesizing the substrates, attributed to Monod, "What's true for E. coli unstable phosphoribosyl derivatives of ATP, is true for the elephant." My fascination with before I could answer any question about gene regulation was also fueled by the NSF eukaryotic operons. My thesis advisor, weekly seminars presented by visiting Norman Giles, turned down my $1500 order scientists from other institutions. I was for PRPP, politely intimating that this was particularly intrigued by one presented by too steep an investment for an untested first Yale's Norman Giles, who was trying to year graduate student. determine whether Jacob and Monod's ideas applied to the regulation of metabolism in With some trepidation, I called Bruce Ames fungi. He suggested that, given my at NIH, already a luminary, and asked him interests, I should come to Yale and work for advice on the synthesis. His response with him. was completely unanticipated. He invited me to come down to NIH and carry out the Pursuit of the Eukaryotic Operon synthesis of these intermediates in his laboratory. He said it would take a week When I began my graduate work in Giles' and that I could stay with him and his wife, laboratory in 1962, the science community Giovanna. He mentioned that efficient was still abuzz with the implications of the synthesis would actually require 2 grams of Jacob and Monod paper. My savvy lab PRPP. When I told him that I could not pay mates, Mary Berlyn and Asad Ahmed, and I for it, he seemed unperturbed and offered to obsessed over every new paper on regulation foot the bill so long as I shared half of the and decided that the most interesting histidine intermediates with his laboratory. question was whether anything like the bacterial operons existed in eukaryotes. To a Bruce's hospitality and enthusiasm made it first year graduate student, the histidine obvious where I would do my postdoctoral pathway in yeast appeared to be the ideal work. Moreover, my successful synthesis of system in which to test for the existence of a these histidine intermediates at NIH allowed eukaryotic operon. Many histidine mutants me to assign each of the genes in the yeast were available in yeast and the organism had histidine pathway to an enzymatic reaction. a tractable genetics. Moreover, Bruce Most of the genes controlling these Ames' laboratory had developed the perfect conversions were unlinked; however, three standard for comparison: in Salmonella all of the steps were localized to a single locus 10 steps in the histidine pathway were (HIS4), leaving open the possibility that encoded in the quintessential bacterial there was an occasional operon in operon transcribed into a single mRNA (2). eukaryotes (3, 4). Bruce's largesse let me finish my graduate work rapidly and in 1965 So, the question was: Were any of the yeast and I headed down to NIH, with my wife, histidine genes organized into an operon? Rosalie, and daughter, Julia. My goal was to learn enough about bacterial operons and of a great laboratory---new ideas evolving protein biochemistry so that I could from the interaction between articulate, determine whether the yeast HIS4 locus respectful, but critical colleagues, who are qualified as an operon. not easily offended. Often no one owns the idea; rather, it is born from the synergy of Postdoctoral Research---The Bacterial the debate. Operon While in the Ames laboratory, I became The Ames laboratory in Building 2 at NIH familiar with the experimental methods used was heaven, but a very small heaven. Bruce to study regulation in bacteria. I discovered and I shared one of his two tiny adjoining that regulation of the histidine operon in labs, which also served as his office. Every Salmonella was intimately connected to the day around coffee time, people from the role of tRNA in Salmonella (collaborating floor would drift in to this cramped often with John Roth and Bob Martin) and lab/office to schmooze. Inevitably, idle published several papers (5-9). As I chatter morphed into a scientific discussion contemplated my future directions, the that could ignite into a heated debate. Bruce excitement of the work on bacteria began to usually provoked the dialogue with a take a back seat to the lure of the unsolved fanciful idea about regulation delivered with operon question raised by my graduate an impish grin: " Suppose regulation really work. works like this." And he would eagerly present his pet conception on a small An Independent Career: Eukaryotic chalkboard glued to the refrigerator door.
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