When once-fresh insights become entwined into the fabric of our common experience, they often lose their original sheen. As we look back with 20/20 hindsight, our understanding of how antibodies bind and recognize antigens may seem to be the only logical way in which these structures could possibly perform their functions. But we assume a lot. The structure and specificity of antibodies presented an enticing puzzle to the great minds in immunology four decades ago. It was here that Alfred Nisonoff made some of his finest contributions. The mind of a chemist turned what was obvious to him into the foundations of what is now obvious to the rest of us.

In a remarkable 1994 interview with G. Kurt Piehler, now in Rutgers Oral History Archives of World War II, Nisonoff revealed his humor, humility and motivations. Born in 1923, Nisonoff grew up a butcher's son who had no intention of becoming a research immunologist. Graduating from high school at the age of 15, he entered Rutgers University on a scholarship, younger and shorter than everyone else. He majored in chemistry and, as he was not yet eligible to be drafted for action in World War II, upon graduation took a job with the US Rubber Company in Detroit. His department tested latex compounds used for adhering cords to rubber for tires, so that they could make aircraft tires with nylon, rather than cotton, cords. While passing through another section of the plant, Nisonoff paused, by chance, to watch self-sealing gaskets being manufactured. In what would turn out to be a characteristic approach, he applied his accidental observations in an innovative manner to the problem his department was having: persuading the nylon cord to stick to the rubber. What seemed simple and obvious to him finally enabled US Rubber to start manufacturing nylon tires. This knack of seeing the obvious, making suitable modifications and then applying it was a skill he put to good use time and again in his pursuit of an understanding of antibody structure and specificity.

In mid-1943, Nisonoff enlisted and served in the Navy, missing the invasion of Okinawa by a month due to engine difficulties. At the end of the war in 1945, he took advantage of the G.I. bill to pursue graduate research in biochemistry with Frederick W. Barnes at the Johns Hopkins University, obtaining his Ph.D. in 1951. It took two more years at US Rubber for Nisonoff to come to the realization that his career would be in biological research. He was introduced to antibodies, a subject that became his passion, by David Pressman at the Roswell Park Memorial Institute in Buffalo. There he initiated his studies of antibody binding to haptens, which led later to his detailed dissection of anti-arsonate idiotypes and to his reputation as the father of “idiotypy”. After 6 years, he accepted a position as tenured associate professor in the Department of Microbiology at the University of Illinois, Urbana. His creativity was recognized by his collaborator Sheldon Dray, who recruited him in 1966 to the University's medical school in Chicago, where he became chairman of the Department of Biochemistry three years later. In 1975 he moved to Brandeis University in Massachusetts. He was elected to the National Academy of Sciences in 1984 and was president of the American Association of Immunologists in 1990–1991.

Throughout his career, the structure and function of antibodies fascinated Nisonoff. He initially approached antibodies with his chemist's careful training and his ability to find the simple solution. During the late 1950s, while he was investigating the biochemical properties of antibody recognition of benzoate derivatives, Rodney Porter and Gerald Edelman, through distinct strategies, determined the fundamental structure of the γ-globulins. Two heavy and two light chains could somehow be cleaved into two univalent antigen-binding fragments, the Fabs, and a non-antigen-binding Fc fragment. At the University of Illinois, Nisonoff also applied the enzymatic approach, but in his own way. Nisonoff's pepsin cleavage studies yielded bivalent antigen-binding fragments called F(ab′)2 and forced the field to rethink the fundamental shape of an antibody, from a unit with a binding site at each end, to the familiar Y-shape that is accepted today. Together, these biochemical examinations provided the underlying framework for our current understanding of immunoglobulin structure.

Understanding structure means having a structure. However, whole IgG was recalcitrant to crystallization. Nisonoff again saw the “obvious” and realized that fragments of antibodies would make a better starting material. His group went on to produce crystals of Fabs, which led to the first high-resolution structure of a Fab with its combining site.

Nisonoff's understated ability to find simple solutions that look obvious in retrospect, and his joy in his pursuits, pushed immunology forward. As Katherine Knight so eloquently eulogized at the Keystone meeting on B cells in April 2001: “His goal was only to learn the truth.”. That he did it with collegiality and humor is why his influence is still felt so profoundly today.