The early years: Working at the bench with Bruce (1957–1959)

Abstract

Having arrived at Rockefeller in the fall of 1958, I began to seek a suitable laboratory to pursue my interest in organic chemistry. The group of Wayne Woolley, together with Bruce Merrifield and John Stewart, seemed to fit my needs, and the presence of a cute technician in Bruce's lab helped to solidify the decision. So I became Dr. Woolley's first (and only) graduate student. The project was to synthesize imidazole derivatives with substrate-specific catalytic activity for the hydrolysis of carboxylic acid esters carrying aromatic side chains. Although the goal of mimicking specific enzyme catalysis was not achieved, I learned a great deal about heterocyclic chemistry. Bruce showed a keen interest in all that I did, and provided more assistance and personal mentoring than anyone else. I married Bruce's cute technician, Sibil Dale, after she left Rockefeller. Her close working relationship with Bruce and her superior memory enable her to write in a more personal account about the early years of Bruce's development of solid-phase peptide synthesis. Sibil's account follows. Bruce gave me my first job when I was just out of college in 1957. I worked as his research technician for 2 years. We shared a lab, along with George Tritch, on the fourth floor of Flexner Hall. The first thing Bruce did in the morning was to turn on the hot water tap to make instant coffee. Once, when I questioned this practice, he replied that he wanted to make sure he got all of his minerals. As soon as I started working with Bruce he taught me some lessons about the cost of research. One day when I was weighing some serine, I poured out too much on the scale and used the spatula to discard the excess in the sink. “You just threw away $65 worth of serine,” Bruce complained. At another time I dropped a sintered glass funnel. Bruce took me down the hall to see Dr. Woolley, the chair of the lab group, who declared that the broken object was worth its weight in gold. Bruce and I worked side-by-side at the same lab bench. As we worked we talked about work, our personal lives, and what we enjoyed in life. Several of us in the department liked to do puzzles while performing such mechanical tasks as evaporating. Bruce stumped us all with his thinking outside the box when one day he came in with the following number puzzle: 42, 51, 59, 68, and asked us what the next number should be. We all assumed it was some kind of mathematical progression and in vain tried to add, subtract, divide, and multiply to identify a pattern. When none of us could find the answer, Bruce announced that these were the subway stops of the Lexington local, a train that many of us, including myself, took to work. It was at the bench that I first heard Bruce mention the idea of linking amino acids into peptides by utilizing a solid support resin. In theory, the concept sounded so simple that I immediately expressed my doubts about the project. I was not the only skeptic. One day, at a graduation dinner, I was seated next to the Nobel Laureate Fritz Lipmann1 who inquired about what Bruce was currently working on. I explained Bruce's idea to Lipmann who said something about bacteria being able to do a much better job. When I repeated this later to Bruce, he seemed amused by Lipmann's comment. Despite the skeptics who surrounded him, Bruce stuck to his idea. I worked with him on the early stages of the development of the project but did not get any positive results. It took Bruce about 3 more years to bring his idea to fruition. In 1963, when John and I were living in Cambridge, England, where John was doing a post-doc, we received a letter from Bruce saying that he had successfully synthesized a peptide using the solid-phase method.