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In 1992, Hungary was in the early stages of extricating itself from the Soviet system following the relatively recent fall of the Berlin Wall and the dissolution of the Warsaw Pact. The country was in a state of excitement tinged with nervousness about what might come next, a mood shared by , then 32 years old. He’d travelled to Budapest that year for the Eighth International Congress of Immunology. Sadelain was there to deliver a presentation entitled, “Efficient transduction of murine primary T lymphocytes,” which meant he was going to talk about the potential for using genetic engineering to treat disease.

It’s not recorded how many of the 5,000 immunologists attending the congress were present at Sadelain’s talk, but he remembers there were enough for it to matter. Part of his excitement had to do with how little the outside world knew about what he’d been up to. No one had introduced a gene into a T-cell for the purpose of treating disease before. In fact, no one had really even posed it as a “what if?” But the idea popped into Sadelain’s head one day in 1986 while undertaking his PhD at the ��������. He carried the idea into his postdoctoral fellowship at the , after he earned his PhD in 1989.

But the Whitehead luminaries, as Sadelain calls them, didn’t think much of his idea. “They thought it was silly,” he told me recently, smiling, when we met for coffee at Tarallucci e Vino on the Upper West Side of Manhattan, where he has lived for many years. The luminaries encouraged him to remain on track with the research duties outlined in his postdoc, which he did, but he worked on his personal project, doing experiments in secret after hours, trying to figure out how to put bacterial genes into mouse T‑cells. For a long time, as much as two years, he had no luck. He pursued his idea undaunted through the early 1990s, and then, one day, just like that, it started to work.

His idea was no longer just an idea. He had managed to attach a bacterial gene to a T-cell.

Which was what he wanted to tell everyone in Budapest. He was there to let the world know that the door to an entirely original and uncharted realm of research had opened just a crack and that what might lie on the other side of that door, if it could be flung open, could change the way the world thought about using genes and cells to treat disease. Sadelain finished his presentation and waited. There was not a particularly enthusiastic response or line of questioning from the crowd. Probably just sober-minded scientists. It was a lot to take in, after all. Responses and inquiries would no doubt come later during the congress, or in the days and weeks to follow. It was reasonable to think it would take time to fully absorb the implications.

In fact, there was no absorption. Not even a flicker of curiosity. The overall reaction to his Budapest talk was, in non-immunologist terms, “Meh.”

Sometimes an idea takes a while to catch on

“I like to tell the story to students now,” Sadelain said. “Because you go to meetings and conferences to present and show your data. That’s what we do in science. But after I presented in Budapest, not a single person came to talk to me. And there were thousands of immunologists there. But people were just uninterested, oblivious. I thought, ‘You don’t understand. Yes, I put a bacterial gene that does nothing in a T‑cell. But I just showed that we can genetically engineer a T‑cell. Now the gates to everything will open.’ That’s what was in my mind.”

Sadly, it wasn’t in anyone else’s mind. No scientist who attended the talk saw the merit in the work. Reflecting years later, Sadelain could only assume that it fit into the philosopher and astrophysicist Thomas Kuhn’s notion of the paradigm shift: that good new ideas always get rejected at first, simply because they don’t fit into the existing paradigm. Sadelain left Budapest and returned to MIT to continue his postdoc, which came to an end in 1994. Paradigm or no paradigm, he needed a job.

In the fall of 2024, Sadelain opened a new clinic at Columbia University after decades at Memorial Sloan Kettering, the research hospital on the Upper East Side of Manhattan where he made his most important breakthroughs. It was a kind of inflection point. Forty years earlier, in 1984, he was at a different inflection point, a crossroads that led him to Edmonton, his mother’s hometown.

After graduating from the ��������, Anne Sadelain (née Doskoch), ’56 BEd, toured Europe. Along with some other young North Americans, she was among the first to enter the USSR in the years after the death of Stalin and the rise of Khrushchev.

“She had family origins in what today is western Ukraine,” says Sadelain. “She was allowed into Ukraine and went to see her family there.” After her travels there and elsewhere, Anne went back to London to regroup with her travelling companions. One of them introduced her to a friend who had managed to leave Poland recently, and didn’t yet know anyone in the UK. His name was Jean Sadelain, and he and Anne fell in love.

Anne returned to Canada to teach for a while, but the couple eventually married and settled in France, “which was the first country to grant refugee status to my father,” says Michel, who was born in Paris in the spring of 1960. Brother Christophe, ’87 BA, and sister Carole, ’94 BA, were also born in Paris.

Michel Sadelain specialized in mathematics in high school and studied medicine at Sorbonne Université. His parents moved to Edmonton in the late 1970s with Sadelain’s siblings, while he stayed in Paris to complete medical school. As he was finishing, one of the ��������’s most prominent immunology professors, Thomas Wegmann, happened to be visiting Paris. He and Sadelain met by chance. Wegmann recognized a scientist with potential and encouraged Sadelain, who was increasingly drawn to research, to come to the ��������.

“It was a real two for one,” says Sadelain. “My mother was already there and I knew that Wegmann was a very good scientist. So I said, ‘Yes, OK, I’ll go and do a short six-month research stint.’”

But shortly after the family had emigrated to Canada, Sadelain’s father became ill. Sadelain himself diagnosed his father with what turned out to be cancer. He had surgery but died two years later.

Sadelain had by then decided to pursue a doctorate at the ��������, and that six-month stint turned into five years. “It was a very fun group of people in immunology,” says Sadelain.

One of those fun people was and now professor emeritus at the Schulich School of Medicine & Dentistry at Western University. In many ways, he became Sadelain’s co-supervisor along with Wegmann, given that Wegmann, as Singh says, “was quite a world traveller.” Wegmann also took a sabbatical during Sadelain’s time at the ��������. “Wegmann was very inspiring, and he had all kinds of projects and programs,” he says. “For Michel, it became a challenge, and I think that’s where he flourished, because he took his own direction. Michel became very independent right at the start of his career in Edmonton.”

At this point in his career, Sadelain was studying immunology, not genetic engineering. But at some point, halfway through his doctoral studies, that big idea popped into his head: Why not engineer T‑cells and put them to work?

The way he explains it, the immune system would sometimes beat cancer but most of the time it lost. One of the greatest immunological tools is the vaccine, which prepares your system to take on future foreign invaders. But a cancer cell is both part of your original system and already present. Which means (or meant, until Sadelain’s work) that the immune system wasn’t equipped to combat cancers. . How did such an idea occur to him? Even he isn’t quite sure. “We read journals, we had clubs, we talked about things all the time,” he says. “And I was reading some papers on the subject one day and I just thought, ‘Wait a minute, why don’t we do this?’”

He shared his idea with others in the program and though they didn’t discourage him, they didn’t exactly encourage him, either. “Mostly, I think they thought it was goofy,” says Sadelain. There were two problems that made it seem insurmountable, or goofy, to others.

The first problem, as alluded to above, was that cancer is not an outsider like a virus, which finds a way in and uses our cells to make copies of itself. Our bodies will recognize a virus, for example, as “other” and mount a defence against it. Cancer is our own cells gone haywire. That’s what makes it hard for the immune system to recognize. Cancer, says Sadelain, “isn’t an invader, it’s one of us.”

The second problem was that no one had ever introduced a gene into a human T-cell before. “Of course, I thought, ‘Yes, that is a tall order,’ ” says Sadelain. “But thinking about things I just thought, how would you go about giving a cell an order and say to it, ‘You, I want you to go recognize that cancer and destroy it.’ Well, the only way would be to have a gene that codes for information that guides the T‑cell to the cancer cells and tells them what to do. How could you confer that property onto a T‑cell? It had to be genetic. Even today, all these decades later, I still can’t really think of a way other than using RNA or DNA.”

Sadelain had more or less decided to become a genetic engineer, a path that would lead him to the Whitehead Institute for Biomedical Research at MIT for a postdoc. It was there he would meet his future wife and research partner, Isabelle Rivière. And it was there he would begin the research that has changed how we think about medicine and disease. Of course, this was just one thing he didn’t know back then.

“Everybody at the Whitehead Institute knew all about genetic engineering,” says Sadelain, laughing. “But before I went there? Well, I wondered how it was carried out.”

It’s iterative

We can say with certainty that Sadelain learned a few things about genetic engineering once he got to MIT. The world now knows him as one of the pre-eminent scientists of his generation. In the last few years, he has won most prizes you can imagine a scientist winning, and , which are sometimes precursors to the Nobel Prize. This narrative makes it seem as if his path has always been leading this direction. But to view his career from the vantage point of today is to misunderstand how science works and downplay how challenging the trajectory of his career was.

To begin with, science is so iterative and collaborative that the concept of a one-moment, one-person “discovery” is more apocryphal than authentic. Sadelain acknowledges regularly how vital his collaborators have been throughout, not least his wife Isabelle Riviére. He has often said that the most important acquisition Memorial Sloan Kettering ever made was her. Numerous stories of their work together recount how it was her scientific acumen that allowed for many of the discoveries they made as a team, particularly at the technical level. In some ways, you could say Sadelain has been the scientific theory lobe of their joint brain and Riviére has been the scientific execution lobe. He has had many other important collaborators and their names punctuate our conversation.

That’s the collaborative part. As for the seemingly straightforward trajectory of his career — well, it hasn’t been that. and a professor at the University of Toronto, has known Sadelain for just over a decade through professional circles, but he’d heard of the work long before. He relays in frank terms how Sadelain’s ideas were received early on. “People were laughing at his ideas at conferences,” says Mattsson. “Think about that. This guy who has changed the way we think about medicine was being laughed at by his peers. It’s like Galileo or something. That level.”

Sadelain himself has a sense of humour about it all. “Actually, I sometimes think that my children must have thought I wasn’t that bright, because I went to school for 17 years after finishing high school. They love to tell the story that their dad had to go to school for 17 years before he finally got a real job.”

“You realize once you start working with him,” says Mattsson, “that he is the most intelligent person you’ll meet. Ever. He’s very Socratic, very polite, but sharp when he needs to be. And always operating with utter clarity.” Mattsson relates the story of Sadelain’s early days as a doctoral student at the ��������. “One of his professors asked him what his goals were for his career and education. People usually say, ‘Oh, I want to be a doctor, I want to do research.’ But Michel said, ‘I want to change the field of immunology.’ I’m sure people looked at him at various points in his career and thought, ‘What the hell are you talking about?!’ But that’s Michel. He’s got that fire to know what he needed, to take the route he knew was best.”

A route without road signs or directions. A route with roadblocks at every intersection. Skeptics and doubters threatened to waylay him even as he started his first job at Memorial Sloan Kettering. By this time, he had fully committed to exploring a realm of genetic engineering that was uncharted, even mostly unimagined, and he chose Memorial Sloan Kettering because it was known for being open to running trials. “It was the right place at the time to test something like this,” he says. “We didn’t even know if we had a potential therapy. We were just hoping, but if we ever got there it was going to be in cancer treatment.”

Incredibly, the two-year struggle to genetically modify a T‑cell during his postdoc at MIT was but a precursor to many more years trying to do the same in a living creature with human cells at Memorial Sloan Kettering. When he finished his postdoc, he was considered a researcher of strong potential, but he was also pursuing something that most experts considered fanciful, a waste of scientific talent. It was as if Connor McDavid — after tearing through the ranks of minor hockey and getting drafted first overall — opted to play pickleball. Why devote yourself to something that would never be useful? This was how many of his peers and the senior scientists in his circle felt about trying to re-engineer T‑cells into cancer-fighters. And it was not only risky in a career sense for Sadelain but for Riviére also, who had by that time gained her own impressive set of credentials.

Hindsight allows us to say he made the correct choice. But in the thick of it, it didn’t look that way. Those years were difficult for Sadelain and Riviére. Sadelain had been hired by one of the world’s leading research hospitals. He’d convinced the love of his life to join him in this quest. He’d made plain to the scientific world, in Budapest, what he was up to. He had clearly rejected standard paths that would have guaranteed him stature, income and comfort. He put careers, status and decades of education on the line for something that he just knew would work. Except then it didn’t. They kept trying. It kept not working. Remember, this was not a matter of days and weeks, but months, then years. For most of the last half of the 1990s, they just kept their heads down, trying, searching, studying, testing, analyzing, poring over every data point to find a way to teach a T‑cell to recognize cancer and eliminate it. Still nothing.

Mattsson says that through these years Sadelain couldn’t even get accepted to conferences to present abstracts on his research. Without the Memorial Sloan Kettering funding, he surely would have gone under, his work lost. People thought he was following a path so misguided that he was imperiling his and his wife’s careers, and those of anyone who worked with them.

“It’s true,” says Sadelain, sipping his coffee at Tarallucci, when I asked him about this. Riviére may have been the best example. They had met at MIT and become life and work partners. After MIT, she moved to a job at New York University, but Sadelain convinced her to join him at Memorial Sloan Kettering. Even when they were still at MIT people warned Riviére to not go with him. “There were those who told her that this work was a career killer,” says Sadelain. “They just said, ‘Well, there is no way this is going to work. You won’t get promotions, you won’t get tenure, you could lose your job.’ It’s true, a scientist needs to produce findings once in a while. If you invest yourself deeply in something for five years, 10 years, great, but you’re not going to get a pat on the back for that. People will say, ‘What have you done?’ It’s high risk.”

Despite the risk, Sadelain pushed forward, with Riviére alongside him. She knew retroviruses, says Sadelain. She knew immunology and was instrumental. “We were really a team,” he notes. There were a couple other people who joined his lab against the advice of peers. Despite the skepticism, Sadelain acknowledges the support of the then-director at Memorial Sloan Kettering, Tom Kelly, who kept Sadelain on staff and funded. Sadelain learned years later that there was significant internal pressure to have him fired and have his T‑cell research shut down as a poor investment.

Sadelain and Riviére had first shown it was possible to genetically modify a T‑cell, and now they were at work trying to get human CD19-directed CAR T‑cells to target and eliminate human cancer cells that had been put in mice. CD19 is a molecule often present in cancer cells. CAR stands for chimeric antigen receptor, a term Sadelain coined, referring to a specially designed protein that’s put onto the surface of T‑cells. . T‑cells are healthy “good soldier” cells scientists take out of the body, re-engineer with the CAR and put back in the body, freshly equipped with instructions to find and eliminate cancer cells by sniffing out the CD19.

OK, but how does it work?

To understand the science behind it, perhaps it’s best to resort to metaphor. Imagine your body is a lake. For some reason, a fish in a corner of the lake starts getting sick and begins to infect the fish and other creatures that contribute to the ecosystem and health of the lake. That sick fish is cancer. What do you do? Well, you could poison the lake (chemotherapy). That would certainly kill a lot of the malignant fish, but that’s pretty hard on the lake, might do more harm than good and doesn’t always work. You could try zapping the sick fish with high-energy beams to neutralize them (radiation therapy), but that doesn’t always zap just the sick fish and can leave some behind. Another option would be to stock the lake with predators (a vaccine or some other medicine) to target the sick fish, but the lake doesn’t tolerate invasive species and often the sick fish are tougher than the predators.

What Sadelain did, on the other hand, was to come up with an idea about using our own cells to affect the disease. In our metaphor, that means taking some healthy fish out of the lake and altering them (putting a CAR into a T-cell) and giving them instructions to make sure the good fish know which are the bad fish (by using CD19 to precisely locate the target for the modified T‑cells.) Then he put the healthy fighting fish (genetically engineered CAR T‑cells) back into the lake to seek out and destroy the bad fish (cancer cells). Even better, he managed to figure out how to get the good fish to reproduce in the lake and keep swimming around looking for bad fish. The lake quite likes its own fish and so it isn’t rejecting any of them. As bad fish are eliminated, the lake (the body!) begins to regain its health.

But it didn’t happen as seamlessly as that. In their trials, they drew human blood, prepared T‑cells, used what are called recombinant retroviruses to transport the gene needed to produce the synthetic molecule — the CAR— that is designed to recognize CD19. Sadelain kept trying to find ways to get the good fish to kill the bad fish in a consistent and flawless manner.

Ideal results kept eluding them, month after month.

Then, one day, doing their normal work pretty much in obscurity, Sadelain and Riviére ran what’s called a flow cytometry analysis to assess the results of a trial. The results came back showing something extraordinary. “We had put human cancers in mice and human T‑cells in the mice,” says Sadelain. And it worked.

Riviére says that she and Sadelain were so nervous and excited and almost in disbelief about the findings that they ran the data through two more times just to be sure. It was “a eureka moment,” she says. Both times the results came back the same as the first. The human T‑cells had blown away the human cancers.

They published the results of their T‑cell work . It caught the world of medical research off guard. Mattsson describes it as a significant moment in human history, because even though no one fully understood the implications at the time, the practice of medicine had just changed profoundly. The trajectory of Michel Sadelain was about to change, too. The whispers of doubt turned into murmurs of amazement.

The years since then have hardly been without event. Sadelain and his team obtained FDA breakthrough designation for a CD19 CAR T‑cells therapy trial and in , including not just remission but long-term survival. Four years later, in 2017, CAR therapies were approved by the FDA for general treatments. The research continues along so many fronts it’s hard to list or categorize them. Ongoing testing and trials have shown that some people treated with CAR therapy as much as a decade ago remain not only cured, but with CAR T‑cells still present in their system. The pharmaceutical industry has become involved to bring the treatment to scale; it is far too expensive a process right now for broad use. Sadelain moved to Columbia University in the fall of 2024, where he’s the inaugural director of the new Columbia Initiative for Cell Engineering and Therapy (CICET) and director of the Cancer Cell Therapy Initiative at the Herbert Irving Comprehensive Cancer Center. From a scientific point of view, CAR therapy is being studied and used in liquid tumours, but the next frontier, Sadelain says, will come with solid tumours of such cancers as breast, brain, prostate and liver.

“And CAR T-cells are now being investigated beyond cancer — for autoimmune conditions, neurological conditions, diabetes, some intractable infections and transplantation complications,” Sadelain says.

The implications of his work are broad. One-third to one-half of people will be diagnosed with cancer or will have someone close to them who has been. “Here you have a man who is showing us how to leave the 20th century behind,” says Jonas Mattsson. “He has changed how we think about medicine. It’s like Michelangelo going to the mountains to find the perfect block of marble to sculpt the David. It was just this enormous piece of stone, but Michelangelo saw the statue inside of it. That’s Michel. He can see things other people can’t. His work is going to impact billions of people.”

People saw this capacity years ago, says Bhagirath Singh. “In my 50 years of teaching,” he says. “I can honestly say that he was the brightest student I ever had. But he also had dedication and motivation, the development of scientific talent to actually understand mechanisms of how things work. But Michel had and has that ability. That’s how you move things forward.”

And it’s not just about talent and intellect, adds Singh. It’s about pure determination.

And yet for all the praise reaching him now, Sadelain remains a scientist. And a scientific field is like a watershed with a dominant river of knowledge that continuously flows towards an ocean of greater understanding. The watershed has countless tributaries of research activity contributing to the river, which never stops flowing.

Sadelain understands this, which is why he can be sanguine about both the importance of his individual contribution and the necessity of having others take part. It doesn’t matter how great your idea is if it doesn’t help anyone, or if the next generation of scientists doesn’t improve on it.

“In some ways,” he says, “it’s about resilience. People might tell you, ‘Oh, that’s a dumb idea, it will never work.’ But you have to keep going. And that’s why curiosity is so important to drive innovative science. For young scientists and students, preserving that is key, because, in the end, it’s all about curiosity and innovation.”