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Meet the A-Team of stem-cell science

From Saturday's Globe and Mail

Nothing about John Dick's accidental entry into science predicted the pivotal role he'd play in reshaping cancer research.

The 49-year-old grew up on a Mennonite farm in southern Manitoba, attended a one-room schoolhouse and set off to Winnipeg to become an X-ray technician. Had he not shared a house with university students studying biology he might never have said to himself: “I wonder if I could do that?”

Even now, sporting a blue tennis shirt in his boxy office in Toronto, with its westward view of an air-conditioning unit, he has none of the trappings of a star scientist.

The only symbols of his success are the 19 bottles of champagne lined up like soldiers along his window ledge. Since researchers often celebrate the publication of big discoveries with a bit of bubbly, his bottles tell the story.

There's the Moët his mentor bought him in 1985 when he showed a stem cell could replenish the blood of a mouse. There's a Brut Imperial from 1988 for the mouse that carried human blood. But there's only one bottle of Dom Pérignon, an '85, popped in 1994 for the paper that's now changing everything.

Dr. Dick's discovery of the first cancer stem cell that year has led to the flurry of recent breakthroughs redefining cancer biology. Scientists once believed all cancer cells could sprout and sustain a tumour. But proof is growing that this deadly power belongs only to a tiny subset of abnormal stem cells that had previously gone undetected. These bad seeds have now been identified as the source of cancers of the blood, breast, bone, prostate, and this week, in another finding from Dr. Dick, the colon.

The implications are staggering. Billions of dollars and decades of research may have targeted the wrong cells to cure the disease. No current treatment has been designed to kill them and they appear to be naturally resistant to the gold-standard therapies.

The work has whipped new optimism into cancer research, but Dr. Dick is loath to take too much credit. “It's rare in science you find something that is completely novel,” said Dr. Dick, who holds the Canada Research Chair in Stem Cell Biology. “Science is like laying a brick wall, one piece is laid over another.”

Science, like any other human endeavour, can be a slave to fashion. From 1975 to 1995, the research world was captivated by the wonder of genes and molecular biology, Dr. Dick said. “Cell biology had fallen by the wayside, and stem-cell research was carried on by a fairly small club of people.”

Starved of the big money available to cancer scientists south of the border, Canadians turned out to be founding members of that club. For fifty years they were “labouring in the shadows,” as one veteran put it, until Dr. Dick's work cemented what the previous generation had suspected.

“They have been the pioneers and they are the clear leaders,” said Max Wicha, director of cancer research at the University of Michigan. “There have been meetings all over the world. People are really jumping into this.”Since studies of embryo development in the 19th century, the idea of a stem cell that gives rise to all the body's tissue types has enchanted scientists. Among them was German pathologist Rudolph Virchow, the fabled father of the autopsy, who in 1855 also wondered whether cancer might not be the spawn of such “embryonic remnants.”

A hundred years later, it was a pair of cancer researchers in Toronto who first proved the existence of the normal stem cell. Ernest McCullough and James Till, working in 1957 at the then-new Ontario Cancer Institute, were interested in questions related to bone marrow transplants.

It seems a radical notion: blast patients with lethal doses of radiation to kill their cancers and then rescue them with infusions of cancer-free donated bone marrow to replenish the blood supply.

Such a therapy would only work if the donated bone marrow contained “seed” cells actually capable of growing an entire blood system. At first, they had assumed there were at least three types of seed cells: one to make red blood cells, another to make white blood cells and a third to make platelets.

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.

Such methods allowed Dr. Dick to look for stem cells among the doses of leukemia he had implanted in the mice. The next question was whether these cells alone were the ones capable of generating the disease. They were.

“We showed we were never able to get leukemia when we transplanted CD34 negative cells, only CD34 positive cells,” Dr. Dick said. What's more, they found these CD34 positive cells could not only renew themselves indefinitely, they could also make other cell types in the disease — the key hallmarks of a stem cell.

It was Dr. Dick's post-doctoral student who convinced him to splurge on the Dom Pérignon when Nature published the paper in 1994.

“Truth be told,” Dr. Dick said, “I didn't have as a good a grip on the literature at the time. I didn't know how it fit in to the big picture. I was just trying to solve the question in front of me, not a 40-year-old dilemma.

“Did I understand that this was a ‘cancer stem cell'? No. It didn't change people's practice, it didn't hit the radar screen.”As far back as 1960, Canadian cancer researchers were holding national meetings to discuss stem cells. The fascination with the subject, Dr. Bernstein suspects, might have had a lot to do with funding — or lack thereof.

Since U.S. President Richard Nixon declared “war on cancer” in 1971, estimates suggest the United States has spent, if adjusted for inflation, about $200-billion (U.S.) on cancer research.

“We never had those deep pockets,” said Dr. Bernstein of the CIHR. While the Americans had the means to make large cancer-cell lines and carpet-bomb them with various anti-cancer agents to see if they could spot a winner, the Canadians contented themselves to look at less expensive questions.

“By not having those resources, we had to do something to get a big bang for a smaller buck,” he said, “so we started looking at cell populations in a cancer.”

Dr. Till agrees with the assessment: “We couldn't afford the brute force of just testing any old molecule that looked interesting. We had to use our wits a bit more.”

The rest of the cancer field had also become less interested in the function of individual cells that make up a cancer, Dr. Till said. The advent of molecular biology, which allowed scientists to penetrate and manipulate a cell's inner machinery, demanded researchers work in bulk.

“One of the characteristics of molecular biology,” Dr. Till said, “is that you have to be able to have large numbers of cells, to grind them up and fractionate them,” to harvest enough DNA and proteins to work with.

But were there concerns the rest of the field might be missing something important?

“There may have been a sense that stem cells were crucial in a tumour, but no one made the leap that the target of chemotherapy might have been all wrong,” Dr. Bernstein said.

“I think the thinking was that chemotherapy drugs are poisonous and if it was poisonous to one cell then it would be poisonous to another, so what did it matter?”

But there is now evidence that chemotherapy, which targets fast-growing cells, may have no effect on a cancer stem cell, which divides slowly.Many researchers initially dismissed Dr. Dick's vintage discovery in 1994 as interesting, but something not likely to apply to solid tumours. Information about normal blood stem cells had been known for decades. But much less was known about normal stem cells in other parts of an adult body, the wizards of regeneration that reline our guts and regenerate our skin every month.

Still, Dr. Dick sensed he was on to something. He started reading, made trips to the library, combed back through the historical literature and the work of generations of Canadian scientists who came before him.

At the same time, the experiments continued and in 1997 he was ready to report the detection of cancer stem cells at the root of three other forms of leukemia. But this time, Dr. Dick pulled no punches, presenting it as the cancer stem-cell hypothesis.

This model says not all cancer cells are created equal, that a pecking order exists in which a master cell, the abnormal stem cell, is the both the key to forming and feeding a cancer. Without an abnormal stem cell, cancers will not grow.

Dr. Dick sent the paper to Dr. McCulloch, now 80 and in poor health, for his input. “Till and McCulloch really set out the principles that we still work under today,” he said of their influence.

Meanwhile, Dr. Till, who happened to train the Manitoba scientist who trained Dr. Dick, said, “I regard him, in the academic sense, like a grandson.”

With the 1997 paper, a few mavericks interested in solid tumours started to sit up and take notice. Soon, younger researchers started turning to Dr. Dick for guidance.Peter Dirks was only two years into his training as a brain surgeon at the University of Toronto when the cold hard fact of his chosen career struck him: Despite all the skills and artistry of the scalpel, “we failed our patients with operations.”

Adults with the most common type of brain cancer, glioblastoma, have a median survival of 15 months. At two years, only one out of four is alive.

“It motivated me to learn biology,” said Dr. Dirks, a slight 41-year-old who looks half his age.

In 1998, he joined the staff of Toronto's Hospital for Sick Children, where too often he had to tell parents they would likely lose their child to a brain tumour. Once again, he felt an urgency to seek solace in a lab.

“It catches you sometimes, you know, when you see a patient who reminds you of one of your own,” said Dr. Dirks, a father of three young daughters.

The heartbreaking scans are on his laptop — brain scans of babies, toddlers and children and the ghostly white images of the tumours he removes, and the tumours that grow back, often within a year.

His own feeling is that tumours are like aberrant organs that just keep growing. But if they could receive the right signals to mature, he says, their growth might stop.

The possibility that a mutant, primitive cell might be the culprit crossed his mind. After all, he noted, in children, brain tumours often form in the fluid-filled space near the centre of the brain where stem cells live. “It is the oldest, most primitive structure in the body.

“I started to turn to John Dick's work, because I thought . . .‘I've got to think outside all of the research that's going on in brain tumours.'”

Dr. Dirks simply knocked on his door and the first time, they spoke for an hour. “I was green . . . and I felt privileged that he would spend that kind of time with a nobody. He was inspirational.”

He decided to hunt for the cancer stem cell behind brain tumours. But the first hurdle he faced had little to do with science. “I had no funding,” he said. The granting agencies could not be swayed.

“It was donations from the families of my patients that kept the research going.”The year before he began his experiment, Dr. Dirks knocked on more doors, making the rounds of Toronto's stem-cell biologists to find out how stem cells from the brain might be grown in the lab.

In one of medicine's most remarkable accidents, it also happened to be a pair of Canadians who solved that puzzle.

In 1989, Sam Weiss and his graduate student, Brent Reynolds, at the University of Calgary were looking for natural proteins to keep brain cells alive. One substance they tested was an epidermal growth factor, or EGF, a protein that boosts development.

They used it as the medium to grow brain cells from adult mice. “The experiment,” Dr. Weiss said, “was a woeful failure.”

But the culture dishes happened to be left in the incubator for a while and after a few days they noticed something peculiar growing: small, suspended clumps on the sides of the dish.

Dr. Reynolds thought they looked like immature cells, not yet grown into their final form.

“I said, ‘nah, it couldn't be, you know what all the literature says on this,' ” Dr. Weiss recalled. The prevailing view had always been that people are born with all the brain cells they will ever have.

But the view was wrong. Dr. Weiss and Dr. Reynolds repeated their accidental experiment “100 times to convince ourselves.” But it looked like proof to them.

The journal Nature turned it down in 1991, saying “it was not of general interest.” But after a few more experiments, Science accepted it in 1992. The report turned medical dogma on its head, proving that the adult brain does not lose the power to make new cells.When Dr. Dirks went back and read the Calgary paper, he knew he'd found the way: The growth factor used to coax the growth of normal adult brain stem cells could perhaps be used to induce brain-cancer stem cells — if they were there — to grow.

Typically, researchers had cultured cells from the brain with bovine serum, a nutrient derived from cow blood. But Dr. Dirks said adding the serum actually prompts stem cells to mature and stop growing.

From the tissue of surgically removed brain tumours, Dr. Dick was able to use a growth-factor cocktail and found that were indeed abnormal stem cells present. These carried the protein CD133 on their surface, the same marker now identified on abnormal stem cells in both prostate and colon cancers.

Dr. Dirks found that that 100,000 ordinary cancer cells cannot grow a brain tumour in a mouse. But as few as 100 to 1,000 cancer stem cells can reliably give rise to the disease.

But as with Dr. Weiss, Dr. Dirks found that publishing what he'd found turned out to be nearly as tricky as discovering it.

“I really had to shop it around,” he said. After taking six months to consider it, Cancer Research published the report in August 2003.

During that time, stem cells was suddenly becoming a hot field.

In April 2003, Michael Clarke at the University of Michigan, who had worked with John Dick on a leukemia experiment, and Max Wicha reported that they had identified the breast cancer stem cell. Using mammary tissue taken from cosmetic breast surgery, they identified that only a tiny fraction of abnormal stem cells were the drivers of those breast tumours.

“That had definitely created a buzz,” said Dr. Dirks, who reconfirmed his finding of a brain cancer stem cell in a live animal model. Three other groups later reported the same discovery.With abnormal stem cells detected at the roots of blood and two solid-tumour cancers, the research field was suddenly forced to take notice. Some scientists began the search for stem cells in their own specialty cancers. Others began to debate their importance.

“There was a meeting around 2003, 2004, where a heated debate broke out about the cancer stem cell hypothesis,” said Jeremy Rich, a neuro-oncologist at Duke University in North Carolina. “It tended to be divided among proponents and skeptics and the more senior the researchers the more likely they were to be skeptical.”

As Dr. Wicha put it: “To people who have devoted their life to chemotherapies and shrinking tumours, this really still has to be proven. Until you show it in people, they are going to be skeptical.”

Dr. Rich said he himself was a skeptic. But after “the elegant work” of Dr. Dirks, he went to stem-cell biologists at Duke (who happen to be a group of Canadians) and began his own experiments. One of them showed brain cancer stem cells can resist radiation.

Dr. Dick divides his time these days between international meetings, the news media and the busy work of his lab.

Peers in his circle say he has been wooed to take up directorships, run institutions. Dr. Dick, however, has “fought it tooth and nail,” never wanting to be too far from the actual science.

Last weekend, his group and another in Italy pinpointed abnormal stem cells as the source of colon cancer. The two reports were both published in advance by Nature. But Dr. Dick said he hasn't even had time to buy a good champagne for the lab team.

Not that there's room on the ledge.

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