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Ralph Marvin Steinman MD (1943 - 2011); Nobel Laureate

December 10, 2018

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History of Medicine
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Ralph M. Steinman MDPhoto credit: By Source (WP:NFCC#4), Fair use, https://en.wikipedia.org/w/index.php?curid=47008779

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 the Rockefeller University. Steinman was one of the recipients of the 2011 Nobel Prize in Physiology or Medicine.

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 (nee Takefman, 1917-2016). The family moved to Sherbrooke, where the father opened and ran a small clothing store called, “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.“

The term “dendritic cells“ was coined in 1973 by Ralph M. Steinman and Zanvil A. Cohn. In 1973, along with his mentor, Zanvil Cohn, Steinman published the discovery of a new class of cell in the immune system - the dendritic cell. Like many new discoveries, his faced a deeply skeptical reception. The experiments couldn't be immediately reproduced, but Steinman was convinced of his discovery. He fought for a decade before immunologists began to broadly recognize the central importance of those cells to their field. Dendritic cells are antigen-presenting cells (also known as accessory cells) of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and the adaptive immune systems. Dendritic cells are present in those tissues that are in contact with the external environment, such as the skin (where there is a specialized dendritic cell type called the Langerhans cell) and the inner lining of the nose, lungs, stomach and intestines. They can also be found in an immature state in the blood. Once activated, they migrate to the lymph nodes where they interact with T cells and B cells to initiate and shape the adaptive immune response. At certain development stages they grow branched projections, like branches of a tree. The word dendrites are from dendron, which is Greek for tree. While similar in appearance, these are structures distinct from the dendrites of neurons. Immature dendritic cells are also called veiled cells, as they possess large cytoplasmic ?veils' rather than dendrites.

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).

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, Dr. Steinman 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. Steinman studied the initiation of antibody responses in tissue culture in the laboratory. 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: Dendritic cells 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 Dendritic cells and lymphocytes. You can actually observe the onset of adaptive immunity in vitro. Dendritic cells were therefore considered “nature's adjuvants“ for T cell immunity, meaning they helped induce T cells. Dendritic cells can produce protective substances like cytokines, interferons, chemokines, anti-microbial peptides Dendritic cells can mobilize innate lymphocytes such as natural killer cells (which in turn produce cytokines or kill target cells upon recognition) However, unlike macrophages, Dendritic cells do not phagocytose or kill microbes. Dendritic cells capture, process and present antigens: - some receptors such as FcR death receptor can activate/inhibit Dendritic cells 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 Dendritic cells 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 Dendritic cells and/or act together with Dendritic cells 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 Dendritic cells 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 Dendritic cells in lymphoid tissues, even in steady (not matured) state. In steady state, Dendritic cells induce tolerance so that Dendritic cell maturation can lead to immunity to microbial antigen - However, maturing Dendritic cells capture microbial as well as self, dying cells, thus resulting in autoreactivity and chronic inflammation.

When Ralph Steinman learned he had pancreatic cancer, the dogged immunologist put his life's work to the test. He launched a life-and-death experiment in the most personal of personalized medicine. By unlucky coincidence, he had been diagnosed with a disease that might benefit from the therapies he had spent his life researching. Usually, medical research proceeds at a glacial, thorough pace: cell studies lead to studies in small animals which lead to studies in larger animals, which eventually lead to small, highly-selective clinical trials in humans. But Steinman didn't have that kind of time. He did, however, have access to world class facilities, cutting-edge technology, and some of the world's most brilliant medical minds, thanks to his position as a researcher at Rockefeller University. So, Steinman decided to make his own body the ultimate experiment. He had removed a piece of the tumor that would eventually kill him. He then trained his immune cells to track down any hint of the tumor that might have escaped the surgery, like putting hounds on a scent. The made-for-Hollywood story of the renegade scientist who fights the establishment to prove his discovery, and then uses it to cure himself, was powerful enough to compel hope. On a Friday, four-and-a-half years after he was diagnosed with a disease that kills the vast majority of its victims in less than one, that experiment came to an end. Steinman died at the end of a week in which he continued his work in the lab. It was a testament to the undying optimism of the scientific enterprise, to the unrelenting man, and to the limits of both. His experiment was an open secret on campus, registered with the hospital and aided by a long-time friend and staff physician. The sense of hope was palpable, bound up in respect for the man but also something broader.

Steinman bet that if he could train his dendritic cells to recognize and tag his cancer, they would be able to convince the T and B cells to do the rest. There was no good reason to expect that Steinman could fashion a cure for one of the world's most vicious cancers in time to save his own life. But it was easy to think it was at least possible. Unfortunately, the dendritic cell-based treatments didn't work - at least not well enough.

One dendritic-cell based vaccine - Provenge - is available now for advanced prostate cancer, leading the way to commercialization for drug makers. Other vaccines are under development

Sources: BBC News, bbc.co.uk/news; bbc.com/news; NIH.gov; Wikipedia

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