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To investigate, Dr. Till and Dr. McCullough transplanted bone marrow from one group of mice to another whose marrow was wiped out by radiation.
Less than two weeks later, the researchers spotted “bumps” on the marrow and spleen of mice that got the transplants and wondered which seed cell had given rise to these growths.
Finding out was no small task. But Andy Becker, a graduate student in their lab, hunched for hours over a microscope and figured out a way to tag cells so that they and all their progeny could be followed.
This way, Dr. McCulloch and Dr. Till were able to follow the transplanted cells, discovering that a single cell inside these lumps — a stem cell — had given rise to the various cell types of the blood system.
“Vivid details of the scene have not been emblazoned on my mind,” said Dr. Till, 75 and now semi-retired. “But I do remember the feeling — it was exhilaration.”
Dr. Dick specialized in microbiology at the University of Manitoba and arrived in Toronto in 1984. He was married with two children and took a part time job in an X-ray lab to pay the bills while he finished his post-doctorate work in the busy lab of Alan Bernstein.
Dr. Bernstein, now president of the Canadian Institutes of Health Research, was then a noted cancer researcher who had trained under Dr. Till and Dr. McCulloch. And it was under Dr. Bernstein's mentorship that Dr. Dick fell, again by chance, into cancers of the blood.
“I didn't know anything about blood at the time,” said Dr. Dick, now a senior scientist with the University Health Network.
But over the next five years, he demonstrated a blood stem cell's ability to replenish the blood system of a mouse, he helped to make an immune-deficient mouse that carried human blood, and he created the world's first mouse with human leukemia.
Dr. Dick might have left it at that. He might have turned to his sick mice and gone on to test leukemia treatments. Instead, “We wanted to know, ‘What are the cells that are actually growing the leukemia in these mice?'” Dr. Dick said. With that single question he became entangled in one of medicine's enduring mysteries: How does a cancer grow?
Tumour cells are never easily grown in a lab dish or a live animal, “or anywhere, period,” Dr. Dick said. Reports dating back to the 1930s also suggested that not all cancer cells had the same power to reproduce a tumour.
In the 1950s, American researchers, in an experiment that would never be allowed today, injected cancer cells from women's breast tumours into their thighs to see if they would “take.” Their conclusion: at least a million cells were needed to grow a new cancer.
More information came in 1963 from Robert Bruce, also at the Ontario Cancer Institute, who showed only 1 per cent to 4 per cent of mouse lymphoma cells could generate a solid growth. In 1973, Dr. Till and Dr. McCulloch found that only one in 100 to one in 10,000 cells could generate myeloma in a lab dish.
So if it was a numbers game, Dr. Dick decided to play it methodically. In an arduous series of experiments, he and his team implanted different quantities of leukemia cells into their special mice to gauge how many were needed to actually grow the disease.
“We put in 10 to the four, 10 to the five, 10 to the six, to the seven,” Dr. Dick recalled. “Only about one in a million cells had the ability to make the disease.
“The thinking was that perhaps you just needed a lot of cells to get it going,” said Dr. Dick, “or maybe the mouse model was fickle or maybe it needed a certain environment.”
Or maybe there was something special about that one-in-a-million cell.By the 1990s scientists knew normal blood stem cells carried on their surface a protein known as CD34. They also developed special antibodies to stick to these proteins so that they could pick them from the rest under a microscope.
As well, high-speed cell-sorting machines had also hit the market, allowing scientists to separate these cells from the others.