Q&A: James Till on the discovery of stem cells

Dr. James Till is not a household name in Canada. Not yet. But as one of the co-discoverers of stem cells, he should be. A Saskatchewan native, Till had been working on radiation therapy for cancer treatment in the early ‘60s at the Ontario Cancer Institute in Toronto, along with another Canadian, Ernest McCulloch (who died last year), when they discovered stem cells. To mark the 50th anniversary of their landmark study published in the journal Nature, Till was honoured at the launch of the Canadian Stem Cell Foundation. Maclean’s had the opportunity to talk to him there.

Q: Can you take us back to the time you found stem cells? What was your eureka moment?

A: The eureka moment was actually when Dr. McCulloch saw the bumps on the spleens of irradiated mice. While those bumps were stem cells, they were bumps of a variety of cells, and when he looked at them in the microscope, he saw in some of the bumps all three kinds of progenitors of mature blood-forming cells. He went, “Hmmm. Ha. That’s interesting!”

We didn’t know where those had come from. They could have originated from clumps of cells, in which case that would not have been very interesting. We made the hypothesis right at the beginning that they might be formed from individuals cells that were producing descendants and would accumulate and form a lump in the spleen. How to prove that? That was challenging. Fortunately we had a talented medical student, and he did it. And the way he did it was to irradiate mouse bone marrow cells. We knew that radiation produced changes to the chromosomes and we had heard that some of those chromosome changes didn’t kill the cells. So he had to see if we could see chromosome aberrations—what we call chromosome markers.

For a while we didn’t find any. And that was kind of disappointing, but then later we did. That was a second eureka moment, but we still had to replicate that and we wanted to see if they would self-renew.

Q: How long did that take?

A: Sometimes you had to wait for 14 days before we’d see any new colonies forming cells. But yes, they self-renewed.

Q: And what did they look like?

A: The results were published in 1963 and, in that paper, we made the first functional definition of stem cells. We didn’t focus on what they looked like. We didn’t care. We used to have a joke: “Well, they’re purple! Why can’t you see them? They’re purple!” What we really did was detect them by what they could do.

Q: So you did have any idea what they could do for medical research?

A: Dr. McCulloch was very interested in bone marrow transplantation for patients with leukemia. He had been involved in the earliest clinical studies in Canada of bone marrow transplant in children with leukemia and unfortunately those were unsuccessful. In fact it took a long time before successful transplants were achieved in adults. For us, the potential for bone marrow transplantation was obvious. The potential for what is now called regenerative medicine wasn’t. It didn’t take off until 1998 when Thompson and Wisconsin showed that embryonic stem cells could be propagated in a cell culture. Then you can multiply these formerly rare cells by growing them in a culture. That raised the possibility that embryonic stem cells could be used for the kinds of things that are contemplated by those interested in regenerative medicine.

Q: Now we have induced pluripotent stem cells (iPS cells), which allow us to make stem cells from adult cells, not embryos. How do you see that?

A: Their potential is still being explored. One hopes that they’re substitutes for embryonic stem cells. But yes, they are fantastic. And totally unexpected.

Q: Why have Toronto and Canada become such a magnet for this kind of research? What are we doing well?

A: Canada is doing very well on very little. So in terms of bang for the buck, Canada is absolutely outstanding in the stem-cell field. It’s a relatively small country on a global scale and also dispersed geographically, so those are two strikes against us in terms of doing leading research. That hasn’t held us back. I guess it started with the subculture within the original Ontario Cancer Institute, which was, unless you’re doing something internationally competitive­, do something else. But it was also an ethos of collaboration and not being afraid of going outside your own discipline. And not being afraid of an agenda that focused on discovery rather than adding another letter to a long scientific word. I think that sort of subculture has stayed with stem cell researchers in Canada.

Q: What is happening now that you’re excited about?

A: My retirement project has been the Internet, the open access movement that has been trying to get primary research literature to anybody, not just the people in the ivory tower, and the other is cancer stem cells. The concept of cancer stem cells has been around for a long time. And McCulloch and I were interested in it when we first began to think about stem cells. I tweet a lot about open access and I tweet about cancer stem cells.

Q: What is the state of research now?

A: Toronto stem cell researchers John Dick and Tak Mak head up groups that have won funding in a competition set up by the California Institute of Regenerative Medicine to take the cancer stem-cell field to the point where a drug can be developed and be ready for regulatory approval. My belief is that they are both capable of doing it. Other than that, can we find a drug that will selectively destroy cancer stem cells? Also, the primary work was done in leukemia, but how about so-called solitude cancers like colon cancer, would it work in other cases as well? There’s been controversy whether that cancer stem cell concept can be generalized to other cancers, all cancers.

Another question is what’s the relationship the cancer stem cells may have initiated, in the tumour, to the metastatic cells that lead to the spread of the cancer outside of the primary tumour? That is the main problem because that’s what kills people, the metastasis. And then there’s the issue of what supports the growth of cancer stem cells, perhaps the so-called microenvironment in which the cancers themselves are located. How much effect does that have? And can you attack that instead of trying to kill the cancer stem cells?

Q: Why has you work has looked so much into cancer?

A: I was asked first whether I would like to do research in biology, which was ecological research and wasn’t appealing at the time. Nuts and berries, that’s not for me. Then a nuclear physicist asked me if I wanted to work for him and I thought, “Hmm, atomic bombs?.?.?.? I don’t know.” This was the time we were very fresh at that. Then I got an invitation from Howard John to work on what was then called hospital physics, the physics of cancer treatment. Now that sounded interesting. It wasn’t blowing anybody up, it’s something I’d like to pursue and that’s how I got into cancer and that’s how I stayed in.

Q: It’s been 50 years since your discovery. Where we are going in the next 50 years?

A: I believe stem cell research will continue to achieve unexpected things and that’s the only prediction I’m willing to make. It will be unexpected because that’s how science functions. And I don’t know when either. I would certainly have not predicted iPS cells, I would have thought that experiment wouldn’t work. It did!