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• W2049752709 abstract "Icame to the Rockefeller University at just about the midpoint in Bruce Merrifield's career. Having completed my Ph.D. training at, using Bruce's words, a “hardcore organic chemistry” laboratory I had not synthesized any peptides by solution or by the solid-phase method. But my graduate adviser, a synthetic chemist, specializing in heterocyclic natural products assured me that this was a good choice for postdoctoral work. Prof. Merrifield was already a world-renowned figure in the field and his invention, solid-phase peptide synthesis, was the wave of the future. As I stepped off the elevator on the fourth floor of Flexner Hall on my first day, I could not ever predict then that I would work in his laboratory until his death more than 25 years later. Bruce Merrifield passed on peacefully in his home in Cresskill New Jersey on May 14, 2006 and brought a close to the life of one of the most creative scientists of our lifetime. He was awarded the Nobel Prize in Chemistry 20 years after the publication of a groundbreaking paper entitled, “Solid-Phase Peptide Synthesis I. The Synthesis of a Tetrapeptide,” in the Journal of the American Chemical Society.1 His invention of solid-phase peptide synthesis revolutionized the field of synthetic chemistry. Those of us who knew Bruce Merrifield will not think of him as a typical revolutionary, although his method met with some resistance from the establishment for many years. Synthesis on a solid insoluble support defied the traditional ways we were trained to set up synthetic reactions. But few will argue now that the method helped blur the boundaries between chemistry and biology and opened up a new frontier for the synthetic chemist. In the Merrifield laboratory, I used the solid-phase method to investigate the structure and function of glucagon, a peptide hormone that plays an important role in glucose metabolism. It is well-documented that elevated plasma glucagon contributed to hyperglycemia in diabetes.2 We believed that if we could segregate the amino acids that were responsible for binding from those that were responsible for activation, we could design novel antagonists of glucagon.3-5 We synthesized over 200 peptide analogues. Moreover, we were able to show in an in vivo study that a peptide analogue that competed for binding to glucagon receptors (GR) but that did not activate the receptor could potentially be used in the management of diabetic hyperglycemia.6 The search for glucagon antagonists by chemical synthesis naturally led to a research endeavor that included the study of the receptor for glucagon. GR is a 483-amino acid seven-helical membrane protein and a prominent member of a superfamily of G protein-coupled receptors. Structure and function studies by site-specific mutagenesis led to new discoveries about GR and its peptide ligand glucagon and put us virtually at the interphase of chemistry and biology.7 Like many chemists, Bruce was initially tentative about molecular biology in his laboratory. Yet he was always eager to discuss what I had learned. We were ultimately interested in obtaining a molecular snapshot of the bioactive conformation of a peptide as it interacted and bound to its receptor protein. As far as Bruce was concerned, we were advancing towards this goal. Most importantly for me, it was an opportunity to expand into a new area independently. The glucagon project continues today. What is most striking about Bruce Merrifield over all of that time we worked together was his consistency. Bruce Merrifield was a man of gentle but steadfast determination. At a time in his career when most scientists have long abandoned lab work, he was determined to take advantage of every opportunity to get back to the bench and remained active in the laboratory until his last years. I have not seen him happier than when he was at work. He remained true to his method and believed there was always room for refinement. The imagery of the American frontier recurs in background when I remember Bruce. To someone not “American-born,” he typified the spirit of America of an earlier time. Bruce was proud of the fact that he was born in Fort Worth, Texas, and still spoke with a very subtle yet unmistakable southwestern drawl. Among memorabilia in his office, a typical Frederic Remington picture hung prominently on the wall facing him. It was that of a small cavalry in full gallop in the brilliant sunlight somewhere in the rugged American western frontier. In the distance, dismounted troopers assumed positions on the ground as their comrades charged forward in a cloud of dust. In the fourth floor seminar room at Flexner Hall, many of us will remember another Remington picture. It depicted a lone native American scout on horseback who interrupted his journey to survey the vast and peaceful landscape before him under a cold but starlit night.8 These images conjured up Bruce's personality as I will always remember him. He was that rare individual who lived each day guided by a simple unwavering set of values that seem foreign to current sensibilities. These were virtues of self-reliance, pragmatism, and dogged determination unencumbered by a pursuit of material needs. Some of us that worked closely with him may have also noted his stubbornness. But it was really a strength of conviction that came from within him. This same inner strength sustained him through the physical difficulties he endured with quiet composure and dignity. He had an unshakeable resolution to finish the work he began some 50 years ago, bolstered by a special satisfaction and pride that comes from hard work, completing a job and doing it to the best of his ability. Even as his passing signaled the closing of the Merrifield laboratory, warm memories of life and science on the fourth floor of Flexner Hall will linger for those of us who have experienced it and who were fortunate to have worked with Bruce Merrifield." @default.
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• W2049752709 date "2008-01-01" @default.
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• W2049752709 title "Merrifield laboratory: Last member standing" @default.
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• W2049752709 doi "https://doi.org/10.1002/bip.20942" @default.
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