The Stem Cell Revolution

FEBRUARY, 1961.
An article is published in Radiation Research by Drs. Ernest McCulloch and James Till, entitled, A direct measurement of the radiation sensitivity of normal mouse bone marrow cells.

FEBRUARY 2, 1963.
McCulloch and Till, with a graduate student, Dr. A.J. Becker, publish Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells in Nature.

DECEMBER, 1963.
Dr. L. Siminovitch, McCulloch and Till publish a third paper, The distribution of colony-forming cells among spleen colonies in the Journal of Cellular and Comparative Physiology.

CUT TO TODAY, 47 YEARS AFTER THAT LAST ARTICLE.

What have come to be called ‘stem cells’ represent a possibility that boggles our minds — that there really could be a serious, realistic way of actually curing the ills that devastate so many people around the globe. Diabetes. Damaged hearts, livers and kidneys. Spinal cord injuries. Cancer. Alzheimer’s disease. Blindness. Parkinson’s disease.

Generations of scientists and hopeful patients have been energized by the promise of Ernest McCulloch’s and James Till’s pioneering work that was described in those articles from the early 1960s.

In medical research, that discovery created a promising vista of wondrous possibilities. And it came from the brilliant work of McCulloch and Till, two University of Toronto professors and scientists at the Ontario Cancer Institute (now the research institute of Princess Margaret Hospital).

In the late 1950s, McCulloch and Till had been conducting research on the effects of radiation on mice, with the intention of transplanting various numbers of bone marrow cells into irradiated mice. Their question: Was there a direct relationship between the number of marrow cells transplanted and the number of mice prevented from dying of bone marrow failure?

“…that had obvious implications for the possibility of nuclear warfare where troops would be exposed to total body radiation and if there could be a bank of normal marrow set aside they might be then subsequently rescued, even after exposure,” Till told CBC Radio’s Bob McDonald in an interview on the Quirks and Quarks program in 2005.

But in conducting that research, McCulloch and Till found something else.

“It came about, as so often happens, as an incidental result on an experiment done for a completely different reason,” said McCulloch in the same interview.

After injecting normal bone marrow cells into the mice, McCulloch and Till later found lumps on the spleens of the mice. The team counted the lumps and discovered there was a linear relationship between the number of cells that had been injected and the number of lumps. In a film for his and McCulloch’s 2004 induction into the Canadian Medical Hall of Fame, Till explained that in earlier experiments, other researchers had seen these lumps and thought they were local areas of regeneration. “We thought of them as colonies of cells.”

“More importantly, they could also look at these colonies,” said Dr. Ronald Worton, former CEO and Scientific Director of the Ottawa Hospital Research Institute, “and say, ‘There are red blood cells in the colony, there are white blood cells…therefore, the one stem cell that lodged into the spleen in the site, must have created all those different cell types.”

Stem cells were not a new idea. “I should point out,” Till told McDonald, “the concept of stem cells had been around for a long time. I mean, it dates back to at least the early 1900s. There was a controversy at that time whether or not there were common progenitors for the various kinds of blood cells because blood cells…like red blood cells, can’t replace themselves…So it was clear they had to be produced by some other kind of cell. That was where the concept of stem cells came from.”

That was it for years — a concept. McCulloch and Till proved the stem cell actually existed. From there, they moved onto the next big step. “We were interested in function. Not what the cell looked like, what could it do? And as soon as that change happened a whole field of science opened up based on function.”

So important was their discovery that McCulloch and Till were awarded the prestigious Albert Lasker Award for Basic Medical Research in 2005. Often referred to as the American version of the Nobel Prize, the Lasker Foundation cited the team for “ingenious experiments that first identified a stem cell — the blood forming stem cell — which set the stage for all current research on adult and embryonic stem cells.”

Their work has resulted in a wave of new work that is redefining what we know and what is possible. “This field of research is exploding,” Janet Rossant told the University of Toronto Magazine earlier this year. Rossant, professor of molecular genetics at U of T and chief of research at the Hospital for Sick Children, is herself a stem cell pioneer, especially in the area of understanding the underlying processes of the early development of the embryo.

“(Stem cell research) is going to be quite revolutionary in the way we think about human disease, allowing us new ways to understand disease, as well as new ways to develop and deliver therapies.”

One of the most recent advances has come by way of the work of Shinya Yamanaka of Kyoto University. In 2006, he discovered that he could reprogram adult stem cells to function as embryonic stem cells — capable of becoming any tissue in the body — by simply adding four genes to the equation.

Within a year, his idea was brought to life when he and his colleagues successfully altered human skin cells back into an embryonic-like state.

Today, hundreds of scientists across the globe are using Yamanaka’s technique — now coined “induced pluripotent stem (iPS) cells.”

Among this group are U of T scientists James Ellis and William Stanford (see page 11) who co-direct the Ontario iPS Cell Facility, an institute that collaborates closely with Yamanaka and his team, and Rossant, who oversees the Ontario Initiative in Personalized Stem Cell Medicine where Yamanaka chairs the external advisory board. The Province of Ontario invested $10 million in the initiative in 2009. And other funding bodies, such as the Canada Foundation for Innovation, have injected millions of dollars into stem cell research, supporting a Canada-wide stem cell community that is enhancing the country’s competitiveness in this hot field.

In fact, it is becoming clear that collaboration is the key to making the tremendous possibilities of stem cell research into real therapies.

“We’ve built quite a stem cell community here in Toronto and there are groups in Ontario and across the country now that are all interacting, sharing research, building on each other’s ideas,” Rossant told Edge. “Because in the end, if we’re going to make a difference, we have to pool our resources. Every group has different strengths and you have to bring them together in different combinations. If we don’t all exchange the best ideas, it will just take us that much longer to make advances. If we want to use iPS cells to develop stem-cell therapies, we need to be working together.”