Ralph M. Steinman
|Ralph M. Steinman|
|Born||Ralph Marvin Steinman
January 14, 1943
Montreal, Quebec, Canada
|Died||September 30, 2011
Manhattan, New York, U.S.
|Alma mater||McGill University (B.S., 1963)
Harvard University (M.D., 1968)
|Known for||Discovery of dendritic cells and its role in adaptive immunity|
|Spouse(s)||Claudia Hoeffel (3 children)|
|Awards||Robert Koch Prize (1999)
Gairdner Foundation International Award (2003)
Nobel Prize in Physiology or Medicine (2011)
|Institutions||Rockefeller University in New York City|
|Academic advisors||Elizabeth Hay (Harvard)
James G. Hirsch and Zanvil A. Cohn (Rockefeller University)
Ralph Marvin Steinman (January 14, 1943 – September 30, 2011) was a Canadian physician and medical researcher at Rockefeller University, who in 1973 discovered and named dendritic cells while working as a postdoctoral fellow in the laboratory of Zanvil A. Cohn, also at Rockefeller University. Steinman was one of the recipients of the 2011 Nobel Prize in Physiology or Medicine.
Early life and education
Ralph Steinman was born into an Ashkenazi Jewish family in Montreal, one of four children of Irving Steinman (d. 1995), a haberdasher, and Nettie Steinman (née Takefman, 1917–2016). The family soon moved to Sherbrooke, where the father opened and ran a small clothing store "Mozart's". After graduating from Sherbrooke High School, Steinman moved back to Montreal where he stayed with his maternal grandparents Nathan and Eva Takefman. He received a Bachelor of Science degree from McGill University and received his M.D. (magna cum laude) in 1968 from Harvard Medical School. He completed his internship and residency at Massachusetts General Hospital.
On October 3, 2011, the Nobel Committee for Physiology or Medicine announced that he had received one-half of the Nobel Prize in Physiology or Medicine, for "his discovery of the dendritic cell and its role in adaptive immunity". The other half went to Bruce Beutler and Jules A. Hoffmann, for "their discoveries concerning the activation of innate immunity". However, the committee was not aware that he had died three days earlier, on September 30, from pancreatic cancer. This created a complication, since the statutes of the Nobel Foundation stipulate that the prize is not to be awarded posthumously. After deliberation, the committee decided that as the decision to award the prize "was made in good faith", it would remain unchanged.
Steinman's daughter said that he had joked the previous week with his family about staying alive until the prize announcement. Steinman said: "I know I have got to hold out for that. They don't give it to you if you have passed away. I got to hold out for that."
Steinman had received numerous other awards and recognitions for his lifelong work on dendritic cells, such as the Albert Lasker Award For Basic Medical Research (2007), the Gairdner Foundation International Award (2003), and the Cancer Research Institute William B. Coley Award (1998). In addition, he was made a member of Institute of Medicine (U.S.A.; elected 2002) and the National Academy of Sciences (U.S.A.; elected 2001).
List of awards
- 1998 – William B. Coley Award
- 1999 – Robert Koch Prize
- 2003 – Gairdner Foundation International Award
- 2006 – Debrecen Award for Molecular Medicine
- 2007 – Albert Lasker Award for Basic Medical Research
- 2009 – Albany Medical Center Prize (Shared with Charles A. Dinarello and Bruce Beutler; )
- 2010 – Heineken Prizes
- 2011 – Nobel Prize in Physiology or Medicine (shared with Bruce Beutler and Jules A. Hoffmann)
Immunology tries to understand resistance to infection. Infections are first resisted by innate immunity, followed by adaptive immunity which has memory and so can prevent reinfection. Two questions that Immunologists ask: 1) by what mechanism do innate and adaptive resistance come about? 2) how do these mechanisms contribute to other fields of medicine such as cancer, allergy, autoimmunity etc.? In the 20th century, he came up with two theories: 1) macrophages mediate innate resistance through phagocytosis and intracellular killing 2) Ab mediate adaptive resistance by neutralizing microbial toxins. Steinman discovered that dendritic cells link innate to adaptive immunity, including adaptive Tcell-mediated immunity.
He studied the initiation of antibody responses in tissue culture in the laboratory. As shown, he found out that antigens, lymphocytes and "accessory cells" together create immune responses. Accessory cells contain a new cell type with probing cell process or "dendrites". These cells proved to be the missing link between innate and adaptive immunity.
Steinman together with Dr. John Leonora demonstrated that dental decay originates as a disruption of the endocrine system that impacts the dentinal fluid and allows bacteria to gain a foothold. This theory challenges traditional theories concerning both oral hygiene and fluoride use.
Several features were used to identify and purify dendritic cells from mouse spleen. Because dendritic cells were discovered amongst "adherent" accessory cells (i.e. those that attach to tissue culture surfaces), they had to be distinguished from macrophages, whose hallmarks were persistent phagocytosis and adherence to tissue culture surfaces. However, Steinman found that dendritic cells (blue) had different morphology and expressed different molecules from macrophages. For example, they did not express FcR- receptors but did express major components of the Major Histocompatibility Complex II and did not adhere to surfaces or exploit phagocytosis. Macrophages on the other hand showed the opposite characteristics. The study was carried out in collaboration with Zanvil A. Cohn, who studied resistance to infectious diseases especially the biology of macrophages.
Some general features of T cell responses that are initiated by dendritic cells: - adaptive immunity develops in two stages: DCs present antigens and initiate the afferent limb, while the other APC mediate the effectors to eliminate the antigen or infection - in tissue cultures, immunity develops in clusters of DC and lymphocytes. You can actually observe the onset of adaptive immunity in vitro. Dendritic cells were therefore considered "nature's adjuvants" for T cell immnunity, meaning they helped induce T cells. DCs can produce protective substances like cytokines, interferons, chemokines, anti-microbial peptides DCs can mobilize innate lymphocyltes such as natural killer cells (which in turn produce cytokines or kill target cells upon recognition) However, unlike macrophages, DCs do not phagocytose or kill microbes
DCs capture, process and present antigens: - some receptors such as FcR death receptor can activate/inhibit DC function - Antigen processing and presentation of proteins and lipids seems efficient and can include cross presentation on MHC I and CD1 - Uptake and processing are regulated by environmental stimuli - In vivo, dendritic cells process antigens to form peptide-MHC complexes in the steady state, especially in lymphoid organs - Most DCs in vivo in the steady state are immature, able to take up and present antigens, but unable to adaptive T cell immunity - Environmental stimuli, e.g., microbial products, alter or mature DCs and/or act together with DCs to control the formation of different types of helper, cytotoxic and regulatory types of T cells - Maturing dendritic cells also carry out innate responses, particularly the formation of cytokines and chemokines - Maturation links innate to adaptive immunity; it controls the quality of the response that develops in DCs and in lymphocytes that recognize presented antigens - "subset" refers to distinct DC with different receptor for antigen uptake and maturation, and distinct functions in innate and adaptive immunity. they reside in the peripheral organs and induce different forms of antigen-specific peripheral tolerance. Antigens from the periphery are captured by DC in lymphoid tissues, even in steady (not matured) state. In steady state, DC induce tolerance so that DC maturation can lead to immunity to microbial antigen - However, maturing DC capture microbial as well as self, dying cells, thus resulting in autoreactivity and chronic inflammation.
- "Rockefeller University scientist Ralph Steinman, honored today with Nobel Prize for discovery of dendritic cells, dies at 68". Rockefeller University. October 3, 2011.
- Steinman RM, Cohn ZA (1973). "Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution". J. Exp. Med. 137 (5): 1142–62. doi:10.1084/jem.137.5.1142. PMC . PMID 4573839.
- Nussenzweig, M. C.; Mellman, I. (2011). "Ralph Steinman (1943–2011)". Nature. 478 (7370): 460. doi:10.1038/478460a. PMID 22031432.
- "January 2008 ASCB Newsletter Member Profile – Ralph M. Steinman" (PDF). Retrieved December 18, 2011.
- "Dendritic cells: from the fabric of immunology" (PDF). Retrieved December 18, 2011.
- "Nettie Steinman". Whereretireestalk.com. April 4, 2011. Archived from the original on January 11, 2012. Retrieved December 18, 2011.
- "Canadian scientist wins Nobel prize days after death". .canada.com. Archived from the original on December 26, 2011. Retrieved December 18, 2011.
- "Bar-Mitzvah of Steinman's brother Mark Charles (Canadian Jewish Review)". Multiculturalcanada.ca. March 24, 1961. Archived from the original on October 7, 2011. Retrieved December 18, 2011.
- "Seymour David Steinman". Google. September 11, 1962. Retrieved December 18, 2011.
- "Canadian Jewish Review: Mark Charles Steinman". Multiculturalcanada.ca. December 17, 1965. Archived from the original on January 18, 2012. Retrieved December 18, 2011.
- "Nathan Zelig Takefman (1891–1965)". Cousinsconnection.com. Retrieved December 18, 2011.
- "Dr. Ralph M. Steinman Receives the 2010 Thomas E. Starzl Prize in Surgery and Immunology". Archived from the original on 2009-02-01.
- "Nobel Prize in Physiology or Medicine 2011" (Press release). Nobel Foundation. October 3, 2011.
- "Nobel winner died days before award announced". CNN. October 3, 2011. Retrieved October 3, 2011.
- "Montreal-born scientist dies before Nobel honour". CBC News. October 3, 2011. Retrieved October 3, 2011.
- "Ralph Steinman Remains Nobel Laureate". The Nobel Foundation. October 3, 2011. Retrieved October 4, 2011.
- Sample, Ian (2011-10-03). "Nobel prize to be awarded to dead scientist". The Guardian. London. Retrieved October 10, 2011.
The Nobel foundation concluded that the award should stand, saying: "The Nobel prize to Ralph Steinman was made in good faith, based on the assumption that the Nobel laureate was alive."
- Orange, Richard (October 3, 2011). "Nobel jury left red faced by death of laureate". The Daily Telegraph. UK. Retrieved December 18, 2011.
- "Debrecen Award for Molecular Medicine". University of Debrecen. Retrieved 7 January 2015.
- Dentinal Fluid Transport. Clyde Roggenkamp. Loma Linda University Press. October 31, 2005