In memory of Ralph Steinman, a gentle giant of immunology

Crucell’s Chief Scientific Officer Jaap Goudsmit pays a personal tribute to the man who discovered dendritic cells.

Ralph Steinman (1943–2011) was awarded this year’s Nobel Prize in Physiology or Medicine for his discovery of the dendritic cell and its role in adaptive immunity. Sadly, Ralph died on September 30, 2011, a few days before the award was announced. Because the decision to make Ralph a Nobel laureate had been taken while he was still alive, the Nobel Committee decided that he would be granted the award posthumously. This is unique in the history of the Nobel Prize.
I got to know Ralph over a period of 18 years. We met for the first time in 1993 and for the last time just months before his death.
In 1993, I took sabbatical leave from my position as Professor of Virology at the Academic Medical Center of the University of Amsterdam and moved to New York with the family for a year. I was appointed visiting professor at the Aaron Diamond Aids Research Center, which was founded by Irene Diamond in 1991 and directed by David Ho, who still heads the center today. A couple of times a week during my first month or so at the center, Ralph Steinman showed up at the lab in the afternoon. I did not know who he was or what he did. David Ho enlightened me: “Ralph is a genius and one of the nicest men I know.”
I found out that Ralph had a lab at Rockefeller University and—very naively—asked him what he did. We were sitting in the conference room of the Aaron Diamond Center drinking coffee. He gave me an incredibly charming smile—that smile is etched is my memory—and explained to me very patiently how he had discovered dendritic cells in mouse spleens.
Ralph’s gentle but inescapable powers of persuasion became evident shortly after. When I arrived at the center, it was affiliated with New York University, but half way through 1993 David Ho shifted affiliation to Rockefeller University––Ralph’s institution.

A discovery that transformed immunology
As soon as viruses attack us and enter our bodies, T cells rush to the place where the action is and do everything they can to eliminate as many virus-infected cells as possible while B cells start to produce antibodies against the virus itself. Up until 1973, nobody understood how this very specific immune response got started.
That’s when Ralph Steinman announced that he had found a completely new type of cell in the peripheral lymphoid organs of mice. He reported his discovery in three consecutive papers, two published in 1973 and the third early in 1974. All appeared in the Journal of Experimental Medicine, which is published by Rockefeller University. That underlines another typical characteristic of Ralph Steinman: his loyalty.
The first of the seminal papers described the unique appearance of these novel cells, found in small numbers in the spleen and lymph nodes. In the last sentence of the summary, a name is proposed for this new cell type: the dendritic cell. The next two papers elaborated on the unique properties of these dendritic cells, or DCs as they came to be known in immunologist jargon.
As is always the case with great discoveries, nobody believed Steinman at first. But in the late 1970s and early 1980s, a series of papers appeared that confirmed the importance of DCs in the adaptive immune system. They had titles like: ‘Lymphoid dendritic cells are potent stimulators of the primary mixed leukocyte reaction’ and ‘Murine lymphoid dendritic cells are powerful stimulators for helper T lymphocytes’.
In 1983, Ralph Steinman and Michel Nussenzweig finally published the paper that hit the nail on the head—again, of course, in Ralph’s beloved Journal of Experimental Medicine. This time, the last sentence of the summary concludes that “DC likely represent[s] the critical accessory cell required for the induction of lymphocyte responses.”
Two decades later, Steinman showed that the efficacy of an investigational vaccine was greatly enhanced by targeting the candidate protein to dendritic cells. This proved that dendritic cells have a key role not only in natural immune responses but also in vaccine-induced immunity.

A pioneer of immunotherapy
In 2006, the Bill and Melinda Gates Foundation launched the Collaboration for AIDS Vaccine Discovery. One of the research grants awarded as part of this initiative was the ‘Comprehensive T cell Vaccine Immune Monitoring Consortium’ headed by Richard Koup, who co-discovered one of the HIV cell receptors. I was appointed as chair of the Scientific Advisory Committee for the T cell vaccine consortium and we asked Ralph to join. Over the past five years we have met in Washington every year.
Ralph was diagnosed with advanced pancreatic cancer in 2007 and immediately decided to prove—using himself as the experimental subject—that cancer vaccines based on dendritic cells work. Ralph received three different experimental vaccines made with his own cells. The first was GVAX, developed by BioSante Pharmaceuticals using irradiated cells from Steinman’s tumor and engineered to attract and activate dendritic cells. For the second, developed by Argos Therapeutics, dendritic cells obtained from Steinman were loaded with RNA extracted from his tumor and injected back into him in the hope of destroying the tumor. The third, from Baylor University, aimed to boost tumor-specific immunity by loading up Steinman’s dendritic cells with peptides present on the surface of his tumor and injecting those cells back into him. None of these approaches saved Ralph’s life, but they may have given him a few more years to enjoy.
When we saw each other at this year’s meeting of the Scientific Advisory Committee, he pointed out to me that the era of ‘true’ cancer vaccines had started in 2010 with the FDA approval of Provenge (Dendreon Corporation), a therapeutic vaccine for prostate cancer. The procedure starts with extraction of the cancer patient’s own dendritic cells, which are loaded up with a fusion protein of a prostate cancer antigen and a cell stimulating factor. The stimulated anti-cancer dendritic cells are then re-injected into the patient in three courses over the span of a month. The survival benefit of Provenge was shown to be several months.
Ralph Steinman was clearly extremely happy and satisfied that 27 years after his discovery of dendritic cells , immunotherapy based on his discovery was here to stay.

November 2011