It would not be at all an exaggeration to say that Marian Koshland’s career was spectacular. She made very important contributions to our field in each and every decade for the past half century. As a graduate student at the University of Chicago in the 1940s Bunny, as she was known, worked on a vaccine for Asiatic cholera. This work not only demonstrated the importance of mucosal antibodies in immunity but also led to her lifelong interest in the structure and origin of antibodies.
By the early 1950s and before the formal definition of antibody classes, Bunny had shown that secreted and serum-borne forms of antibodies were discrete molecules. By the 1960s, she began to address one of the central problems in immunology—the origin of antibody specificity. There was a raging debate between instructive models, which held that antibody proteins were all the same and just folded around their target antigens, and selective models, which argued that they were the products of different cells. Bunny analyzed polyclonal antibodies directed against two different haptens, and on the basis of exquisitely careful amino acid composition analyses, convincingly showed that these antibodies had different amino acid compositions and therefore must differ in their amino acid sequence. These data had a profound effect on theories of antibody formation and how antibody specificity was generated. Legend has it that at the annual meeting of the American Association of Immunology where she first presented her data, her talk was received by a standing ovation—quite high praise indeed. By the end of the 1960s, Bunny’s work had become part of the mainstream of an emerging idea that is now one of the cornerstones of immunology, that is, that antigen receptors, both of T cells and B cells, are encoded by multiple rearranging gene segments. Her work in this area was seminal. Charlie Janeway, who is currently the president of the American Association of Immunologists, recently commented that he had a clear memory of the time in medical school when he first read Marian’s papers in this area, and that it was for him a defining moment that motivated him to embark on a career in immunology.
By the 1970s, Marian had returned to her studies of secreted versus serum-borne antibodies. She identified a novel antibody subunit called the J chain, characterized it, and showed that it played a central role in antibody assembly and secretion and that the beginning of its expression marked a clear, discrete step in the maturation of B cells. This work led to the central theme of the remainder of her scientific career: understanding the way in which a B cell becomes an active player in the immune response.
In the late 1970s, Bunny did a sabbatical stay in David Baltimore’s lab at MIT to learn molecular biology, as she felt that the future of the field lay in this area. While at MIT she collaborated in cloning the gene encoding the J chain and brought the gene and her knowledge of the emerging technology of molecular biology back to the immunology group at Berkeley. In the 1980s Bunny turned her attention to regulation of transcription of the J chain gene by B cell growth factors. By 1990s her work had extended to the more general area of events that accompany and direct B cell activation and maturation. In an invited talk at the national meeting of the American Association of Immunologists in 1997, she presented a wonderful description of recent work from her lab demonstrating that the action of a transcription factor, BSAP, was very complex and dynamic, and that it could have both positive and negative effects: extinguishing some genes whose products were no longer needed, while turning on new genes with roles important to the emerging antibody-producing arm of the immune system. This talk was a marvel, and put together complex biochemical phenomena in an understandable context of biological function. It was a testament not only to the quality and timeliness of her own work, but also to how far the field has come in a detailed understanding of the workings of the immune system in the half century since Marian entered it.
In honor of all of her accomplishments, Marian received awards that are much too numerous to completely list here. She was elected to the National Academy of Sciences, the American Association of Arts and Sciences, and to the Council of the American Association of Immunologists, which she served as President in 1982–1983. She received the FASEB Excellence in Science Award. She served on many committees of the National Institutes of Health and the National Science Foundation involved in setting national scientific policy, including the NIAID Advisory Council and the National Science Board. She was noted for her courage and straightforwardness in speaking her mind, and for her honorable positions on emerging issues.
If there is any single feature that marked Bunny’s work, it was her ability to reduce complex phenomena to experimentally addressable components. She did this by putting a very high emphasis on experimental rigor and absolute scientific integrity. She was not affected by fads in science, but only by the bottom line—how well hypotheses hold up to hard experimental scrutiny. Bunny was well known for her impatience for and willingness to challenge half-baked ideas. I am sure that there are many immunologists who, like me, can recall times when we were forced to defend our hypotheses to this formidable devil’s advocate. Bunny was not at all shy in attacking and probing every assumption, every finding, every control. Merely surviving an encounter with Bunny always gave me confidence that I could defend my ideas to anyone.
Marian served as an inspirational role model for women pursuing careers in science. In a field that was clearly dominated by men during the early stages of her career, she demonstrated that a woman could have a spectacular career while successfully managing to raise a family. It is in part for this that she was honored by the AAI Committee for the Status of Women in Science at a special symposium held at the annual Meeting of the American Association of Immunologists this year.
Reading back over some of Marian’s works recently, I noted that in a memoir she wrote for the Annual Reviews of Immunology she said that she chose science as a career in part because of her conviction that science is a way of making lasting, if not immortal, contributions to mankind. The legacy that Marian has left us, in her own scientific achievements as well as those of the students and the fellows that she has trained and those of her colleagues like myself on whom she had a strong influence, will indeed be very long lasting. She is, and will be, missed for a very long time by all who knew her and learned from her.