“In the early nineties, pioneering steps were taken in the use of mRNA as a therapeutic tool for vaccination. In the following decades, an improved understanding of the mRNA pharmacology, together with novel insights in immunology have positioned mRNA-based technologies as next-generation vaccines.”Three decades of messenger RNA vaccine development
Like teenagers the world over, Nobel Prize-winning scientist Ralph Steinman had absolutely no idea what he wanted to do when he grew up.
In a 2009 essay, the Canadian-born immunologist and cell biologist described his early school career as unfocused, only landing on an interest in biology and medicine while taking “almost every other course” at McGill University in Montreal while on scholarship as an undergraduate.
This latent interest eventually led him to Harvard Medical School, where he earned his M.D. (also on scholarship), and an internship and residency at Massachusetts General Hospital. In 1970, the young Steinman joined the Laboratory of Cellular Physiology and Immunology at Rockefeller University in New York City as a postdoctoral fellow under cell biologist and immunologist Zanvil A. Cohn. Steinman wanted to know what triggers the body’s immune system to kick into gear to initiate a response, a question few scientists at the time were asking.
Just three years later, while working with cells from the spleens of mice, Steinman and Cohn made the discovery that would shape Steinman’s future: the identification and role of a particular type of white blood cell that sets into motion and controls the body’s immune system. They termed these cells dendritic cells, after the branching, tree-like shape the cells can form.
By identifying this chief component that initiates and regulates an immune response, Steinman had discovered why, when, and how the body’s immune system reacts the way that it does, especially in the face of foreign pathogens. He’d discovered what amounted to the boss cell that kicks off immune reactions and tells other cells what to do and what not to do. Dendritic cells also play a role in autoimmune diseases, inflammation, allergies, and transplant rejections.
This discovery would revolutionize immunotherapy and eventually launch the new field of dendritic cell biology. But at the time, Steinman’s discovery was generally disregarded. Dendritic cells were considered little more than an obscure anomaly by much of the scientific community. To top it off, the cells were difficult to isolate, and low in frequency and abundance to boot. It would take more than 20 years and Steinman’s development of a new method to generate large numbers of dendritic cells for experimental use for the scientific community to finally verify and accept his theories.
Steinman was especially interested in clinical applications for dendritic cells, dedicating much of his career toward the development of new medical therapies and treatments based on his research. His discovery led to the first therapeutic cancer vaccine in 1973, a dendritic cell-based immunotherapy for the treatment of prostate cancer. Other potential immunotherapies that have resulted include cancer and transplantation treatments and vaccines for HIV, malaria, tuberculosis, and the Epstein-Barr virus, some of which have reached clinical trials.
Steinman’s desire to see his research put into practical medical application cannot be overstated. Despite his gentle, almost grandfatherly way of speaking, he often expressed frustration at the slow speed at which experimental therapies escaped the confines of the lab and its theoretical animal and data models to reach actual patients. This impatience took on a new sense of urgency in 2007 when Steinman was diagnosed with Stage 4 (advanced) pancreatic cancer. By the time of his diagnosis, the cancer had already advanced beyond the pancreas and spread to Steinman’s lymph nodes. His chances for surviving another year were estimated at less than five percent.
So, Steinman went to work. In response to his illness, he designed and coordinated a single-case medical study with himself as the sole subject.
In addition to undergoing conventional surgery and chemotherapy, Steinman reached out to the international network of researchers in industry and academia he’d built over his decades-long career. Banding together for this common cause, he and his colleagues developed a variety of personalized cancer treatments, many based on his design and research, including vaccines developed from Steinman’s own tumor cells.
Despite his general impatience with the speed of the traditional scientific process, Steinman insisted on conducting his personal trial according to established protocols, filing mounds of paperwork with official channels and seeking appropriate permissions for untested therapies just like any other trial. Although his personalized experiment was not controlled, he wanted it well-organized and well-documented so his treatment attempts might not only find a cure for himself but also gather knowledge that could be used to benefit others.
This adherence to protocol, however, became a source of frustration for some of Steinman’s colleagues. Steinman, for example, refused combined therapies that failed to get regulatory approval, even though he and many of his colleagues felt the combined approach had a higher likelihood of success. He also initially refused to undergo multiple treatments at once because doing so would confuse the data being collected. With time of the essence, colleagues had to argue with Steinman to get him to prioritize the possibility of his health and longevity over proper protocol and clean experimental results. All told, Steinman underwent as many as eight experimental therapies, in addition to surgery and chemotherapy, to combat his disease.
During his long career, he received numerous awards and honors, including the prestigious Lasker Award (sometimes referred to as the American Nobel) in 2007. While in the midst of his illness and self-experimentation, he was also nominated for the 2011 Nobel Prize in Physiology or Medicine for his discovery of the dendritic cell and subsequent contributions to immunology research and medicine.
Steinman joked often about surviving long enough to witness the awards announcement, and as late as a week before, the possibility seemed likely. But on September 30, 2011, four and a half years after his cancer diagnosis, he died just three days before the Nobel Prize announcement. He was 68 years old.
Nobel Prize rules generally prohibit the awarding of a prize posthumously, but given the unusual circumstances and unfortunate timing of events, the Nobel Committee ruled to allow the honor to stand. Steinman shares the prize with American immunologist Bruce A. Beutler and French biologist Jules A. Hoffman, also for their work in the area of immunity research.
Although no one can be sure of the efficacy of the dendritic cell-based immunotherapies Steinman underwent or which one(s) might have helped, the Nobel Laureate lived more than four times longer than expected. His decades of work have contributed to clinical therapies for cancer and infectious diseases that will benefit patients for generations to come. And despite those early years of unfocused study, even his self-experimentation laid the groundwork for future treatments, including an immunotherapy against pancreatic cancer based on data gathered during Steinman’s final experiment. – Folks Magazine
Ralph Steinman died days before it was announced that he was to share the Nobel Prize for Medicine. His work had been part of an unorthodox experiment to save his life, wrote Politico journalist Brett Norman, quoted by BBC, 2011.
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 personalised 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 tumour that would eventually kill him. He then trained his immune cells to track down any hint of the tumour that might have escaped the surgery, like putting hounds on a scent.
On 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.
An open secret
I joined Rockefeller as a science writer to chronicle the work of its researchers – Steinman included – about halfway through one of his experiments on himself.
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.
Could the painstakingly incremental research that seemed to have so much potential on lab animals this once grant a reprieve from certain death?
Of course everyone was rooting for him, and I had a special interest. Toward the end of 1999, my father had a stomach complaint. Over a few months, the initial diagnosis of an ulcer morphed into a death sentence: inoperable, metastatic cancer of the pancreas.
Pancreatic cancer is often known as the “silent killer” because it usually doesn’t produce truly scary symptoms until it has spread beyond repair. After chemotherapy, my dad bounced back for a few months, but the cancer inevitably did, too. He died at home in the early fall of 2000.
Could Steinman beat it?
I hoped so. The work had promise.
“In the last few years of his life, Dr. Ralph Steinman made himself into an extraordinary human lab experiment, testing a series of unproven therapies – including some he helped to create – as he waged a very personal battle with pancreatic cancer.”– Reuters
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 sceptical 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 recognise the central importance of those cells to their field.
In the past 20 years, the study of dendritic cells has spread to hundreds of labs all over the world. Researchers are exploring how they might be harnessed to fight cancer, HIV and transplant rejection, among other major medical problems.
Dendritic cells are the “sentinel cells” of the mammalian immune system. Named after the Greek word for tree, they develop distinctive probing branches when activated, sweeping their environment in search of unwelcome things – like bacteria, viruses, tumours.
When dendritic cells encounter something they don’t like, they take a physical marker of the invader, called an antigen, and present it to B and T cells, the defenders of the body’ s immune system. Those cells then adapt weapons to identify and destroy the interlopers.
Steinman bet that if he could train his dendritic cells to recognise 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. 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.
Unfortunately, the dendritic cell-based treatments didn’t work – at least not well enough.
Training Steinman’s dendritic cells to the tumour did generate a “vigorous immune response to mesothelin, a tumour specific antigen,” said Dr. Sarah Schlesigner, a longtime colleague of Steinman’s who ran the trial.
In other words, while there were significant side effects, the therapy seemed to enable him to work much longer than he otherwise would have. Month after month, he remained at the University, continuing his work.
He survived much longer than expected, and continued his research until the end.
Over time, it wasn’t enough.
At least, not enough to save him.
But the research he pioneered continues – and the scientists who continue his work have an extraordinary example to follow. – BBC, 2011
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