Ralph M. Steinman: A man, a microscope, a cell, and so much more

Ralph Steinman died from complications of pancreatic cancer on September 30, 2011, an event even more sad because it occurred a few days before he could hear the announcement that he was to receive the highest public recognition for the accomplishments of his truly remarkable career in biomedical research, the Nobel Prize in Physiology or Medicine, for his discovery of the dendritic cell and its role in adaptive immunity. It is a devastating loss not only for his family, friends, and colleagues but for the much broader scientific community. Ralph was a basic scientist par excellence, but his impact was far greater, in part because he never lost sight of his training as a physician and the need to translate advances in basic science to the prevention and treatment of human disease.

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Ralph Steinman at The Rockefeller University circa 2001.

Ralph was born in 1943 in Quebec, the son of an immigrant family from Eastern Europe. He received his B.S. degree with honors in 1963 from McGill University and his M.D. degree magna cum laude in 1968 from Harvard University, and completed a residency in Internal Medicine at Massachusetts General Hospital. This was a time when the fundamental principles of immunology were first being illuminated, and he was absorbed by the conundrum that the precision with which the immune system can respond to pathogens and transplanted tissues could be so readily demonstrated and measured but the mechanics of how such responses were initiated—what tells the immune system to respond—were largely unknown. Because phagocytic cells, and particularly macrophages, were thought to be critical for capturing and presenting antigens to kick-start the immune response, Ralph made the decision in 1970 that would shape his career, to leave his medical training and join the laboratory of Zanvil Cohn and James Hirsch, who were developing and applying the tools of modern cell biology to study phagocytic/endocytic functions, at The Rockefeller University, the institution where he would remain for his entire career. One of those tools, the microscope, became his instrument for defining truth, and he was never very far away from one. It now seems prescient that, decades ago, Ralph prominently placed in his laboratory a larger than life-sized picture of Ilya Metchnikoff, who won the Nobel Prize in Physiology or Medicine for visualizing and describing phagocytosis and perceiving its importance in host defense, to peer incessantly over those who entered the laboratory, reminding young investigators and visitors how science gets done. While searching for cells that could initiate the immune response, Ralph and Zanvil Cohn identified and described in 1973, in the first of a series of five classic publications in the Journal of Experimental Medicine, a “new” glass-adherent cell, detected as a rare component of spleen cells, that appeared morphologically and biologically distinct from macrophages, in part by its inability to phagocytose particles. They termed this cell a dendritic cell for the probing, tree-like shapes it formed in the microscope (from the Greek dendron, meaning tree). To paraphrase Humphrey Bogart from Casablanca: this was to be “…the beginning of a wonderful friendship” between Ralph and this remarkable cell that was to revolutionize immunology. However, it was not a smooth road, and many in the scientific commu-nity were very skeptical, questioning if this cell was either an artifact or merely a macrophage dressed up in a new suit.

Ralph was, if dismayed, undaunted by the controversy and pursued the singular strategy he always demanded of laboratory members and colleagues to “just do the experiment,” and the data ultimately not only erased the skepticism but created a whole new field in immunobiology. The biggest early obstacle, beyond gaining acceptance by his peers, was defining how such nonphagocytic dendritic cells with no detectable antigen on the cell surface could be presenting antigen to initiate a T-cell immune response. The problem was further magnified by the landmark studies of Doherty and Zinkernagel in 1974, demonstrating MHC restriction of T-cell responses, because this ultimately meant that antigens had to get inside the antigen-presenting cell to be inserted into MHC molecules before being transported to the cell surface for recognition. However, this quandary, like many he would face, was resolved by elegant cell biology studies from his and many other laboratories demonstrating both the highly specialized receptors and the unique intracellular pathways that dendritic cells use to take up, process, and present antigens, as well as the additional receptors dendritic cells express that can trigger maturation. Dendritic cells thus are uniquely capable of activating T cells if the milieu in which the antigens are encountered informs these dendritic cells of potential danger to the host, for example, in the context of receiving signals by their Toll-like receptors, discovered by Jules Hoffmann and Bruce Beutler, who share this year’s Nobel Prize in Physiology or Medicine with Ralph. There were many more critical discoveries, including the demonstrations that dendritic cells can pick up antigens in peripheral tissues and at mucosal surfaces, and can then acquire the ability to migrate to lymph nodes to bring those antigens to a place where T cells reside, and that many subsets of dendritic cells with distinct and specialized functions and capabilities exist. Ultimately, these studies have all served to prove and extend Ralph’s original premise that dendritic cells are the cells vital for initiating the cellular immune response, for not only providing the antigen to resting T cells but for instructing the T cells to respond, and for influencing the quality as well as the magnitude of the response. From this, the principles of modern vaccinology have evolved, including the current focus on strategies to deliver the desired antigen to dendritic cells and promote maturation of the dendritic cell to efficiently induce the desired response.

Ralph emphatically believed that dendritic cell science could and should be used to prevent and combat disease, and he was passionate about the need to pursue translational studies and perform research in humans to prevent and treat infections, cancer, and autoimmunity. He felt strongly that such essential research was underappreciated and underfunded, in part because the term translational research was too often perceived as implying the simple implementation of advances in basic science to the clinic rather than giving research in humans its rightful and critical place in the discovery equation. He was greatly concerned that clinical scientists struggled to maintain and advance careers because of biases by the elite journals that interpreted clinical studies as lacking the mechanistic depth derived from studying laboratory organisms, by funding agencies ill-prepared to review proposals constructed in the context of the obstacles and difficulties in human research, and by academic institutions that relied on traditional standards of productivity for promotion. Ralph championed these causes, promoting the careers of young clinical investigators, encouraging foundations and the National Institutes of Health to develop programs to recognize and support clinical investigation, and helping create a special niche for human research in the Journal of Experimental Medicine.

At a Keystone meeting I cochaired a few years ago, we asked Ralph to deliver, in addition to his plenary talk, the keynote to wrap up the meeting. He said the talk would be on “gaining traction on translation,” and joked that although it would be philosophical, it would not be Kirkegaard. How true this was, as Ralph and his perceptions for scientific discovery and application could never be confused with existentialism. He fervently believed in the importance of fostering frequent interactions and collaborations between laboratories and institutions, and that solving big problems required creating a whole much greater than the sum of its parts. As a colleague, Ralph could be highly critical and very supportive in the same sentence. As a friend and collaborator, he could be demanding while being fiercely loyal and caring. Ralph’s work revolutionized how we think the immune system works and how it can be modulated, created new fields of scientific endeavor, and is already leading to new therapies for human disease, with a deep pipeline to follow. The absence of his continued contributions, insights, and motivation will be an immense loss, because he broadened the lives and improved the research of so many investigators, and the scientific community is now a distinctly smaller and less rich place. However, most of all, he will be greatly missed by his colleagues, friends, and especially his family, to whom he was so devoted and from whom he received so much love and support.