RETROSPECTIVE

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

Philip D. Greenberg1 Departments of Medicine and Immunology, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024

alph Steinman died from com- could be presenting antigen to initiate plications of pancreatic cancer on a T-cell immune response. The problem RSeptember 30, 2011, an event was further magnified by the landmark even more sad because it occurred studies of Doherty and Zinkernagel in a few days before he could hear the an- 1974, demonstrating MHC restriction of nouncement that he was to receive the T-cell responses, because this ultimately highest public recognition for the accom- meant that antigens had to get inside plishments of his truly remarkable career in the antigen-presenting cell to be inserted biomedical research, the Nobel Prize in into MHC molecules before being trans- Physiology or Medicine, for his discovery of ported to the cell surface for recognition. the dendritic cell and its role in adaptive However, this quandary, like many he immunity. It is a devastating loss not would face, was resolved by elegant cell only for his family, friends, and colleagues biology studies from his and many other but for the much broader scientific com- laboratories demonstrating both the highly munity. Ralph was a basic scientist par specialized receptors and the unique in- excellence, but his impact was far greater, tracellular pathways that dendritic cells Ralph Steinman at The Rockefeller University in part because he never lost sight of circa 2001. use to take up, process, and present anti- his training as a physician and the need gens, as well as the additional receptors to translate advances in basic science dendritic cells express that can trigger mat- to the prevention and treatment of for visualizing and describing phagocytosis uration. Dendritic cells thus are uniquely human disease. and perceiving its importance in host de- capable of activating T cells if the milieu Ralph was born in 1943 in Quebec, fense, to peer incessantly over those who in which the antigens are encountered in- the son of an immigrant family from entered the laboratory, reminding young forms these dendritic cells of potential Eastern Europe. He received his B.S. investigators and visitors how science danger to the host, for example, in the degree with honors in 1963 from McGill gets done. While searching for cells that context of receiving signals by their Toll- University and his M.D. degree magna cum could initiate the immune response, Ralph like receptors, discovered by Jules Hoff- laude in 1968 from Harvard University, and Zanvil Cohn identified and described mann and Bruce Beutler, who share this and completed a residency in Internal ’ in 1973, in the first of a series of five classic year s Nobel Prize in Physiology or Medi- Medicine at Massachusetts General Hos- publications in the Journal of Experimental cine with Ralph. There were many more pital. This was a time when the funda- critical discoveries, including the demon- Medicine,a“new” glass-adherent cell, de- mental principles of immunology were first strations that dendritic cells can pick tected as a rare component of spleen cells, being illuminated, and he was absorbed by up antigens in peripheral tissues and at that appeared morphologically and bio- the conundrum that the precision with mucosal surfaces, and can then acquire the logically distinct from macrophages, in which the immune system can respond to ability to migrate to lymph nodes to bring part by its inability to phagocytose par- pathogens and transplanted tissues could those antigens to a place where T cells be so readily demonstrated and measured ticles. They termed this cell a dendritic cell reside, and that many subsets of dendritic but the mechanics of how such responses for the probing, tree-like shapes it formed cells with distinct and specialized functions were initiated—what tells the immune in the microscope (from the Greek den- and capabilities exist. Ultimately, these system to respond—were largely unknown. dron, meaning tree). To paraphrase Hum- studies have all served to prove and extend Because phagocytic cells, and particularly phrey Bogart from Casablanca: this was Ralph’s original premise that dendritic “... macrophages, were thought to be critical to be the beginning of a wonderful cells are the cells vital for initiating the ” for capturing and presenting antigens to friendship between Ralph and this re- cellular immune response, for not only kick-start the immune response, Ralph markable cell that was to revolutionize providing the antigen to resting T cells but made the decision in 1970 that would immunology. However, it was not a smooth for instructing the T cells to respond, and shape his career, to leave his medical road, and many in the scientific commu- for influencing the quality as well as the training and join the laboratory of Zanvil nity were very skeptical, questioning if magnitude of the response. From this, the Cohn and James Hirsch, who were de- this cell was either an artifact or merely principles of modern vaccinology have veloping and applying the tools of modern a macrophage dressed up in a new suit. evolved, including the current focus on cell biology to study phagocytic/endocytic Ralph was, if dismayed, undaunted by strategies to deliver the desired antigen to functions, at The Rockefeller University, the controversy and pursued the singular dendritic cells and promote maturation of the institution where he would remain for strategy he always demanded of laboratory the dendritic cell to efficiently induce the his entire career. One of those tools, the members and colleagues to “just do the desired response. microscope, became his instrument for experiment,” and the data ultimately not Ralph emphatically believed that den- defining truth, and he was never very far only erased the skepticism but created a dritic cell science could and should be away from one. It now seems prescient whole new field in immunobiology. The that, decades ago, Ralph prominently biggest early obstacle, beyond gaining ac- placed in his laboratory a larger than life- ceptance by his peers, was defining how Author contributions: P.D.G. wrote the paper. sized picture of Ilya Metchnikoff, who won such nonphagocytic dendritic cells with The author declares no conflict of interest. the Nobel Prize in Physiology or Medicine no detectable antigen on the cell surface 1E-mail: [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.1119293109 PNAS | December 27, 2011 | vol. 108 | no. 52 | 20871–20872 Downloaded by guest on September 29, 2021 used to prevent and combat disease, and traditional standards of productivity for big problems required creating a whole he was passionate about the need to promotion. Ralph championed these cau- much greater than the sum of its parts. As pursue translational studies and perform ses, promoting the careers of young clinical a colleague, Ralph could be highly critical research in humans to prevent and treat investigators, encouraging foundations and very supportive in the same sentence. infections, cancer, and autoimmunity. He and the National Institutes of Health to As a friend and collaborator, he could felt strongly that such essential research develop programs to recognize and support be demanding while being fiercely loyal was underappreciated and underfunded, clinical investigation, and helping create and caring. Ralph’s work revolutionized in part because the term translational re- a special niche for human research in the how we think the immune system works search was too often perceived as implying Journal of Experimental Medicine. and how it can be modulated, created new the simple implementation of advances At a Keystone meeting I cochaired a fields of scientific endeavor, and is already in basic science to the clinic rather than few years ago, we asked Ralph to deliver, in leading to new therapies for human dis- giving research in humans its rightful and addition to his plenary talk, the keynote to ease, with a deep pipeline to follow. The critical place in the discovery equation. He wrap up the meeting. He said the talk absence of his continued contributions, was greatly concerned that clinical scien- would be on “gaining traction on trans- insights, and motivation will be an im- tists struggled to maintain and advance lation,” and joked that although it would mense loss, because he broadened the lives careers because of biases by the elite be philosophical, it would not be Kirke- and improved the research of so many journals that interpreted clinical studies gaard. How true this was, as Ralph and his investigators, and the scientific community as lacking the mechanistic depth derived perceptions for scientific discovery and is now a distinctly smaller and less rich from studying laboratory organisms, by application could never be confused with place. However, most of all, he will be funding agencies ill-prepared to review existentialism. He fervently believed in the greatly missed by his colleagues, friends, proposals constructed in the context of the importance of fostering frequent inter- and especially his family, to whom he was obstacles and difficulties in human research, actions and collaborations between labo- so devoted and from whom he received so and by academic institutions that relied on ratories and institutions, and that solving much love and support.

20872 | www.pnas.org/cgi/doi/10.1073/pnas.1119293109 Greenberg Downloaded by guest on September 29, 2021