On 30 September 2011, just days short of the announcement that he had been awarded the Nobel Prize for his discovery of dendritic cells, Ralph Steinman lost his nearly 5-year-long battle with pancreatic cancer. Although this disease claims the lives of 85% of those it afflicts within 1 year of diagnosis, it was not surprising to many of us who knew him that Ralph beat the odds for so long and got so much accomplished while doing so.
Ralph was born in 1943 in Sherbrook, Quebec, to Jewish immigrants from Eastern Europe. As is true for many children of immigrants, he chose to forsake the family owned business (a general store) and strike out in a new direction—medicine. After graduating from McGill University, he attended Harvard Medical School and became interested in how the immune system protects against disease. After completing internship and residency training at the Massachusetts General Hospital, Ralph chose to pursue a career in science and joined the laboratory of Zanvil Cohn and James Hirsch at The Rockefeller University in 1970. The Cohn- Hirsch lab had a remarkable and long history at Rockefeller. It was originally headed by Oswald Avery, who discovered the transforming principle (that DNA is the genetic material), and later by Rene Dubos, who discovered the first antibiotic, Gramacidin, and was the mentor of Hirsch and Cohn. Long before “translational science” became a catch phrase, Avery was one of the few who actually combined basic science with a focus on implications for elucidating fundamental disease processes. Ralph embraced this tradition enthusiastically.
The focus of the Hirsch-Cohn lab was on cells of the innate immune system, particularly the macrophage and its role in defense against infectious agents and as a mediator of inflammation. The approach was not limited to immunology but embraced cell biology and biochemistry, an influence that proved to be a defining one for Ralph.
In the early 1970s, it was becoming clear that adaptive immune responses were triggered by “antigen-presenting cells” and that the responses were restricted by molecules of the major histocompatibility complex (MHC). Antigenic peptides were shown to combine with MHC to produce a complex that serves as a ligand for specific T cells. Given their central role in innate immune responses and ability to capture and degrade invading microorganisms, it seemed logical that the macrophage would also play the central role in antigen presentation. Ralph characterized how macrophages handled antigens, and his fi ndings had ripple effects far beyond macrophage biology. He found that macrophages (and other cell types) continuously internalized membrane during endocytosis, but recycled it intact back to the cell surface. Yet, antigen internalized by macrophages was efficiently degraded in lysosomes, seemingly at odds with the formation of peptide-MHC complexes.
Ralph and his colleagues determined that the cell actually responsible for antigen presentation was not a macrophage but a distinctive cell type with long dendrites that was rich in MHC molecules but poor in lysosomes (as compared with macrophages). Electron microscopy revealed a morphologically similar cell in lymphoid organs, which was eponymously referred to as the “dendritic cell” (DC). Ralph led an intrepid and dedicated group of colleagues to develop methods to culture DCs, isolate them, and characterize their properties and functions. Given that they were far less numerous than macrophages in the initial preparations, and given that the zeitgeist of the field assumed that the T cell stimulatory functions Ralph had ascribed to DCs were actually the purview of macrophages, gaining acceptance for this concept was a long uphill battle. The opposition may have helped contribute to the incredible elegance and incisiveness that characterized Ralph’s work, but it also led to career challenges and personal disappointments. Ralph’s unbelievable level of dedication, courage, and stubbornness, combined with wonderful support from his family and from Cohn, enabled the DC ultimately to come into its own and join the pantheon of the most important cells in the immune system.
Ralph’s infectious enthusiasm and scientific leadership was inspiring to increasingly large numbers. Not only his former students and fellows but also many others in and around immunology were drawn to the study of DCs. As a result of Ralph’s work, that of his collaborators, as well as an entire new field born of his efforts, we now understand that the DC is the key player in driving immunity. It is essential for the initiation of virtually all antigen-specific adaptive immune responses, and provides the missing link between the innate and adaptive arms of the immune response. DCs capture microbes, bear the pattern recognition receptors for microbial components that cause DC “maturation” (the process that converts DCs from antigen-capture mode to antigen-presentation mode), and secrete the cytokines that polarize T cell responses accordingly. The conceptual framework forged by Ralph’s discovery and analysis of DCs is profound.
Recognition finally did come for Ralph, in the form of the highly prestigious Gairdner and Lasker Awards in 2003 and 2007, and most recently by the Nobel Prize, which he sadly never got to see. Nevertheless, this affirmation was deeply meaningful for those who knew him and those influenced by his contributions to science.
It is rare in the modern history of biomedical science to be able to attribute the discovery of a new cell type, much less a transforming new conceptual understanding, to a single individual. Ralph Steinman clearly provides one such example. His life and work were characterized by a singular dedication first and foremost to his family, his work, and to his friends and colleagues.
SOURCE : SCIENCE MAGAZINE VOL 334