Science, Science and Tech

Obituary: Ralph Steinman

Ralph Steinman, who has died of pancreatic cancer at the age of 68, was an illustrious figure in the field of immunology. Not only did he discover a new class of cells, he pioneered a new approach to the development of vaccines and immune-based therapies for infections, autoimmune diseases and cancer, including his own.

Alongside his mentor Zanvil Cohn, Steinman discovered the missing link between antigens and lymphocytes, previously unknown cells that effectively mediate the immune response. He named these cells “dendritic cells” after their tree-like structure but had to fight for a decade before other immunologists recognised the importance of his discovery. Due to this tenacity and belief in his work, the study of these cells has spread to hundreds of labs the world over during the past 20 years, revealing more about their remarkable capabilities.

As a young scientist, Steinman was deeply interested in understanding how the incredible processes of the immune response began. This area of research led him to Rockefeller University in 1970, and it was there in 1973, whilst studying the spleen cells of a mouse, that he stumbled across the answer. Previous research had already revealed that the induction of the immune response required lymphocytes (white blood cells, in particular B- and T-cells) and “accessory cells”, which were unidentified but thought to be typical macrophages (large phagocytic cells). Steinman was surprised to find cells with unusual shape and movement: their most distinctive feature was their many processes (protuberances) constantly probing the environment. They were very different from macrophages in terms of membrane enzymes, life cycle and structure, along with being poorly phagocytic. He concluded that these were a new class of cells with their own distinctive properties. By 1979, he had learned how to enrich populations of dendritic cells, which were generally very small, and functional studies began, revealing more about their stimulatory role in the immune system. Comparable cells were found in other organs and species, including human blood. By 1992, with the help of colleagues in Europe and Japan, Steinman developed methods to create large numbers of dendritic cells, which greatly expanded research.

The features and roles of dendritic cells have now been greatly established. They are found in lymphoid and immune organs, as well as the interface between the body and the environment. The epidermal layer of skin has a rich network, as do the surfaces of the airways and intestines. Their basic function is to sweep the environment for bacteria, viruses, tumours and other invaders, take antigens (physical markers) to T-cells and alert them to the presence of injury or infection. T-cells then go on to create the immune response, involving B-cells to produce antibodies if necessary. Dendritic cells have a tentacular shape and are constantly moving. Their branching, tree-like form fits their function: snatching invaders and embracing other immune cells to deliver antigens and signals. One analogy Steinman used likened the immune system to an orchestra. Different types of cells are like different musicians, each with different talents. Dendritic cells are the conductors, instructing each cell when and how to play. An effective immune response is the symphony.

New research has shown that dendritic cells also play a seemingly opposite role: that of  immune tolerance. They suppress immune cells against harmless antigens from the body’s own tissues, preventing the body from attacking itself. During infection and cancer, microbes and tumours can exploit this feature in order to evade immunity. However, dendritic cells can also capture antigens from these intruders and generate resistance, which is where Steinman’s later research focused.

Steinman wanted to develop vaccines in a new way, utilising the functions of dendritic cells. The optimistic innovator saw new possibilities in the fight against Aids and cancer in chemically defined substances that would be safe, specific and incisive. A marked feature of dendritic cells is their apparent intelligence: the ability to process different invaders, find the appropriate lymphocytes and conduct their responses. It is this analytical nature that he hoped to exploit in the treatment of his own cancer. After being diagnosed four and a half years ago, he turned his own body into an experiment, attempting to train his dendritic cells to recognise and tag his cancer. Although the treatment was not very efficient, it did produce a vigorous immune response which enabled him to selflessly continue his work  with a disease that takes most lives within a year. Although not enough to ultimately save him, the research he pioneered continues.

The life of this dedicated scientist began in Montreal, Canada. He undertook his undergraduate studies at McGill University, which is where he says he became smitten with science. He graduated with a BSc with honours in 1963 and went on to complete his MD (magna cum laude) at Harvard Medical School in 1968. This was followed by internship and residency at Massachusetts General Hospital, after which he joined Rockefeller University as a postdoc. He gradually rose from the position of assistant professor to director of the Christopher H Browne Centre for Immunology and Immune Diseases.

Alongside his research, which also included HIV and allergies, he fulfilled many other roles: editor of the Journal of Experimental Medicine, scientific adviser to several organisations concerning cancer, and member of the National Academy of Sciences, as well as the Institute of Medicine. He was the recipient of numerous scientific awards, including the Albert Lasker Award in 2007, the Albany Medical Centre prize in Medicine and Biomedical Research in 2009, the AH Heineken prize for Medicine in 2010, and most recently the Nobel prize in Physiology or Medicine in 2011. The Nobel prize was shared with two other biologists also researching the immune system, Bruce Beutler and Jules Hoffman. Sadly, the announcement came three days after his death, and although the award is not usually given posthumously, the decision remained unchanged.

He leaves behind his wife, Claudia, and their three children Adam, Alexis and Lesley.


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May 2021
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