A shopkeeper’s son from Sherbrooke
Ralph Marvin Steinman was born in Montreal on January 14, 1943, the second of four children in an Ashkenazi Jewish family. His father, Irving, was a Jewish immigrant from Eastern Europe; his mother, Nettie (born Takefman), was the daughter of a Montreal family. Soon after Ralph was born the family moved to Sherbrooke, in Quebec’s Eastern Townships, where his father opened and ran a clothing store called Mozart’s.
Irving Steinman hoped his son would join the family business, but in high school Ralph fell in love with science. After graduating from Sherbrooke High School he moved back to Montreal to study, living with his maternal grandparents, Nathan and Eva Takefman. He earned a bachelor’s degree with honours in biology and chemistry from McGill University in 1963.
Harvard and the pull of research
Steinman went on to Harvard Medical School, graduating magna cum laude in 1968. While there he spent a year as a research fellow in the laboratory of the cell biologist Elizabeth Hay, who introduced him to cell biology and the immune system. He completed his internship and residency at Massachusetts General Hospital in Boston, where he met Claudia Hoeffel, a medical social worker. They married in 1971 and had three children, Adam, Alexis and Lesley.
Clinical medicine did not hold him. In 1970 he joined The Rockefeller University in New York as a postdoctoral fellow in the Laboratory of Cellular Physiology and Immunology, led by the physician-scientists Zanvil Cohn and James Hirsch. The laboratory had been founded by the microbiologist René Dubos, who believed that to understand infection one must study the host as well as the microbe. Steinman would spend his entire career at Rockefeller, becoming a full professor in 1988 and director of its Christopher H. Browne Center for Immunology and Immune Diseases in 1998.
A strange new cell
In the early 1970s the immune system was thought to work through two main kinds of cells: lymphocytes, which recognise specific invaders and make antibodies, and macrophages, scavengers that swallow microbes. Everyone in the Cohn laboratory studied macrophages. But a central puzzle remained: what actually starts an immune response? Lymphocytes alone, taken from the spleen and placed in a dish, responded poorly to foreign substances. They needed help from some other “accessory” cell.
Studying cells from the spleens of mice, Steinman noticed an unusual cell that stuck to glass like a macrophage but looked and behaved differently. It did not swallow particles, and it constantly extended and pulled back long, branching arms. In 1973, in a paper with Cohn in the Journal of Experimental Medicine, he described this previously unknown cell type and named it the dendritic cell, from the Greek word for tree, because its arms resembled bare branches.
Proving the sentinel
Steinman suspected the new cells were the missing link that switches on immune responses. In 1978, with Margit Witmer, he showed in cell culture that dendritic cells were extraordinarily potent at stimulating T cells, the lymphocytes that direct the immune response and form immunological memory, far more so than macrophages. Many immunologists were sceptical, and for years his claims met silence and even ridicule. He became the cells’ tireless advocate, lobbying colleagues and producing experiment after experiment.
An important step came in 1985, when he and Gerold Schuler showed that Langerhans cells, long known in the skin, mature into powerful dendritic cells, linking his discovery to the body’s outer barrier. Researchers came from around the world to learn from him; the Japanese immunologist Kayo Inaba, who joined his laboratory in 1982 after hearing him speak in Tokyo, recalled that few people then believed dendritic cells could both start and regulate immune responses. Over the following decades his laboratory and others showed how dendritic cells work. Immature dendritic cells sit in places where microbes enter the body, such as the skin and the lining of the gut, sampling their surroundings. When they capture a foreign molecule along with danger signals from an infection, they mature, travel to the lymph nodes and present fragments of the invader to T cells, launching a targeted attack. In the absence of danger, the same cells help teach the immune system to tolerate the body’s own tissues. Dendritic cells, in other words, decide whether the body fights or stands down. By the mid-1990s the scientific world had come round, and the field of dendritic cell biology he founded had grown enormously.
From the laboratory to patients
Steinman was a physician at heart and wanted his discovery to help people. Techniques his laboratory developed for growing and handling dendritic cells in the laboratory made it possible to design vaccines and therapies that use or target these cells. He explored dendritic cell approaches to transplant rejection, autoimmune diseases such as type 1 diabetes and multiple sclerosis, allergies, tumours and infections. In 2010 he launched, at the Rockefeller University Hospital, a first clinical trial of a vaccine against HIV designed to target dendritic cells directly.
When the Nobel Prize was announced in 2011, the committee said the discoveries had made possible new methods for preventing and treating disease, including improved vaccines against infections and attempts to stimulate the immune system to attack tumours, and had helped explain why the immune system sometimes attacks the body’s own tissues. Therapeutic vaccines based on dendritic cells and other antigen-presenting cells have since been tested against many cancers, and one, for advanced prostate cancer, was licensed in the United States. Understanding how dendritic cells are switched on also guides the design of ordinary vaccines and the additives that make them work better.
A clinical trial of one
In March 2007 Steinman was diagnosed with pancreatic adenocarcinoma, a cancer that had already spread and that few patients survive for more than a year. He decided to fight it with the cells he had discovered. Working with colleagues around the world, he designed a series of dendritic cell-based immunotherapies for himself; Rockefeller University Hospital created a special protocol, and he became what the university called a clinical trial of one. Alongside surgery and standard chemotherapy, he received eight successive experimental immunotherapies, and samples of his tumour were shared with laboratories worldwide to tailor them.
For four and a half years he remained largely well, kept working, travelled and lectured. His physician cautioned that no conclusions can be drawn from a single patient, but noted that he enjoyed a longer and healthier life than the odds would suggest.
The prize he never heard about
Ralph Steinman died on September 30, 2011, at the age of 68. Three days later, on October 3, the Nobel Assembly announced that he would receive half of the 2011 Nobel Prize in Physiology or Medicine “for his discovery of the dendritic cell and its role in adaptive immunity”, the other half going to Bruce Beutler and Jules Hoffmann. The committee did not know he had died. Nobel rules forbid posthumous awards, but because the decision had been made in good faith, the Nobel Foundation decided, for the first time, that the prize would stand. According to his daughter, he had joked the week before that he needed to hold out until the announcement.
On October 10, more than 300 colleagues from around the world gathered on the floor of his new laboratory to remember him. His family donated the entire prize money to charity, giving $500,000 to the Cohn-Steinman Professorship at Rockefeller and $250,000 to the Steinman Family Foundation to support young scientists and science education. He had already received the Gairdner Foundation International Award in 2003 and the Albert Lasker Award for Basic Medical Research in 2007, among many other honours.
Family, faith and character
Steinman’s story is that of many Canadian Jews of his generation: a father who came from Eastern Europe and built a small business, a close extended family in Montreal, and a son whose education carried him into the professions and beyond. He spoke little in public about religion, and the accounts of his life focus on his family, his laboratory and his patients.
Colleagues remembered a forceful personality with boundless energy who was nonetheless objective, optimistic and never seemed discouraged. His first question when meeting a colleague was usually “What new findings?” He trained more than a hundred students and postdoctoral fellows from around the world, published some 450 papers, and for decades helped edit the Journal of Experimental Medicine. He was a keen jogger, hiker and skier who packed running shoes for every scientific meeting. Friends abroad kept a pair of his shoes waiting for his next visit.
Legacy
Before Steinman, immunologists could describe the soldiers of the immune system but not the officer who gives the order to attack. His discovery of dendritic cells answered that question and created a whole field of research. It underlies modern efforts to build better vaccines, to turn the immune system against cancer, and to calm it in autoimmune disease and transplantation.
In 2012 the Ralph M. Steinman Center for Cancer Vaccines was established in his honour at the Baylor Institute for Immunology Research in Dallas, and in 2016 Sherbrooke, the town where he grew up, named a new street rue Ralph Steinman. His final years, spent using his own discovery against his own cancer, remain one of the most moving stories in modern medicine.
Sources & further reading
Ralph M. Steinman, Biographical, NobelPrize.org · Press release: The Nobel Prize in Physiology or Medicine 2011, NobelPrize.org · Nobel laureate Ralph Steinman dies at 68, The Rockefeller University · Kayo Inaba, Ralph Steinman 1943–2011, Journal of Clinical Investigation · Ralph M. Steinman, Wikipedia · Researched from the sources above and checked against them. Spotted an error? Tell us.
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