JOE SORNBERGER

Almost 45 years after their breakthrough discovery, two septuagenarian Toronto scientists - revered within their field of stem cells but largely unknown outside of it - have won North America's most coveted prize in medical research the Lasker Award.

James Edgar Till, 74, and Ernest Armstrong McCulloch, 79, proved the existence of stem cells while toiling away at the old Ontario Cancer Institute labs on Sherbourne St. Their breakthrough 1961 paper on the formation of what were then called colony-forming cells is regarded as the starting point for the science. That paper, and several that followed, also provided the scientific underpinning to bone-marrow transplantation.

Public recognition, however, has largely eluded them. "Both James and I are private people," the soft-spoken but droll McCulloch said in one of the interviews conducted with the pair last week and last year. "We do not seek celebrity."

After all these decades, however, celebrity may be looking for them Winning the Lasker - begun in 1946 by philanthropists Albert and Mary Woodard Lasker, and known as "America's Nobel" - is often the prelude to capturing the Nobel Prize Since 1946, 70 Lasker winners have gone on to win the Nobel Prize, including 19 in the past 15 years.

The men will be honoured Friday in New York, sharing a prize of $50,000 (U.S.). Calling Till and McCulloch the "Fathers of Stem Cell Research," today's Lasker Foundation's announcement makes the global impact of their discoveries clear "Their work laid the foundation for all current work on adult and embryonic stem cells and transformed the study of blood-cell specialization from a field of observational science to a quantitative experimental discipline." They also "explained the basis of bone-marrow transplantation, a procedure that prolongs the lives of people with leukemia and other blood cell-cancers."

While happy to be so honoured, McCulloch wished it had happened "10 to 15 years ago" when his health was better and his legs were stronger, "so that I could really enjoy it."

Till speculated that controversy around "just about everything to do with stem cells - stem-cell science, stem-cell ethics, stem-cell politics - the whole bit" might have been a factor in the delayed recognition of their work.

Stem cells are master cells that provide the source material for all organs and tissue. They are found in the embryo and as "adult" cells throughout the body - in the blood, skin, muscle and intestines. Because of their regenerative capabilities, stem cells have the potential to treat or cure a number of debilitating diseases such as muscular dystrophy, blindness, Alzheimer's, Parkinson's, arthritis and diabetes, as well as spinal cord injures and blood disorders. The subject of embryonic stem cells, however, has been controversial, with religious groups decrying the use of potentially life-creating organisms for medical science.

While Till and McCulloch stopped doing research together decades ago, they have remained close friends and still have offices a few paces apart at Princess Margaret Hospital.

They have always been a scientific odd couple. McCulloch, a short, stocky man given to wearing academic tweeds and his Order of Canada pin, is affectionately referred to by friends by his childhood nickname, "Bun." He comes from Old Toronto Scottish stock but is anything but dour. He reads widely (from Jane Austen to Mordecai Richler), is a keen observer of the world around him (he appreciates baseball but thinks hockey is "just people running around on skates"), and believes the best thing that ever happened to Toronto was the post-war influx of immigrants that brought style and culture - and better restaurants - to what had been a "nasty, narrow-minded" city.

Till, at least a head taller than his former research partner, is as neat as McCulloch is rumpled. The son of Alberta homesteaders, he went from studying science at the University of Saskatchewan to a doctorate in biophysics at Yale "because they just kept giving me scholarships." He never worried about taking on difficult challenges with his research because, "I knew I could always go back to the farm." He prefers curling to golf, retains a self-deprecating prairie boy charm, and laughs easily and loudly.

The two were brought together by Harold Johns, who ran the physics division at OCI when it began operations in 1957. Johns thought Till's hard-headed, check-everything-twice, physics-based style of science and his experience with measuring radiation would be a good counterweight to McCulloch's big-picture, what-if conceptual approach. To this day, Till defers to McCulloch as the big thinker, saying he "rode Ernest's coattails," although he will agree to instilling a degree of rigour in their work.

How they discovered stem cells is a research legend.

"We were in the salt mines," said McCulloch, who recently published a book about the early days at the OCI. "The centre of the world was the Toronto General Hospital, and we had been exiled to Sherbourne Street. It was the best thing that ever happened to us. There was no one looking over our shoulders."

Back then, in a Cold War world eager for information on how to survive nuclear war, they were brash, young men studying the effects of radiation on mice.

"One has to consider the context of the time," said Till. "This was the late-1950s, early 1960s. The memories of Hiroshima and Nagasaki were still fresh. There was much concern about the threat of nuclear weapons, that we might have to fight an atomic war. So, being able to ameliorate the effects of total-body irradiation by having a bank of marrow was a big deal. Some of our very early funds came from the Defence Research Board of Canada. They were very interested in this when other agencies were less excited. I still feel a debt of gratitude to that agency."

One Sunday afternoon in 1960, McCulloch stopped into the lab to check an experiment he was conducting injecting mice with cells from bone marrow. He noticed bumps growing on the spleens of the mice, and observed a "linear" match with the number of marrow cell doses. Till agreed they might be on to something colony-forming units originating from single cells.

Said Till "Of course, being able to find what were the active cells in that bone marrow - well, you can imagine being able to purify that and bank those. Whoa! That was the underlying area of applied rationale."

Their 1961 paper in the little known journal Radiation Research went largely unnoticed. Their 1963 follow-up in Nature, however - made possible by the brilliant work of a young researcher named Andrew Becker - showed that the colonies originated from single "multipotent" cells. It changed everything. Essentially, stem-cell science had begun.

Irving Weissman, one of the top stem-cell scientists in the U.S. and the first person to isolate stem cells, views their work as vital and deserving of wider recognition. "I'm delighted that Till and McCulloch got the Lasker," he said.

"I worked hard to make sure they were nominated and appreciated. Their work in 1961 was a great inspiration to me and a number of future stem-cell researchers. I took their evidence that there had to be blood-forming pluripotent or multipotent cells as the stimulus for our isolation of those cells in mouse and man."

Till and McCulloch continued to do ground-breaking work throughout the '60s and '70s, some of it with Canadian genetics pioneer Lou Siminovitch, and trained the next generation of cellular scientists in the process. Their work propelled Canada into the front ranks of the new field. The good job they did encouraging up- and-coming researchers - such as Alan Bernstein, now the president of the Canadian Institutes of Health Research - eventually led Till to leave the field in the 1980s.

"I didn't want to compete with them for grants and resources," said Till. "And Ernest had gone on to much more practical research with leukemia."

Bernstein said the fact it took so long for the pair to be recognized is proof of how far ahead of their time they were.

"The public now knows about stem cells," said Bernstein, whose early research at OCI was supervised by Till. "In those days, it was not considered leading edge. It was definitely not on the international science radar screen. But, to Jim and Bun's credit, they knew it was important. They were not interested in fads and fashion. They were interested in doing beautiful science, important science."

He compares the Till and McCulloch partnership to that of American biochemist James Watson and British biophysicist Francis Crick - the incongruous pair who worked out the double helix structure of DNA in the early 1950s.

"Jim basically knew nothing about blood cells. McCulloch knew basically nothing about colonies and clones and cell division - he was a pure and simple clinician interested in blood cancers. It was the two of them coming together as a team that allowed them to make the fundamental insights on stem cells.

"The discovery that they made - at the cellular level - is as important as what Watson and Crick did at the molecular level. And it's finally being recognized. It's terrific for them and terrific for Canada."

Michael Rudnicki, the scientific director of Canada's Stem Cell Network, said Till and McCulloch are bona fide science heroes. "They are absolutely an inspiration. It was minimal technology - they worked it out with their brains."

He said that if Till and McCulloch were working at Harvard or Columbia they would likely have won the Nobel Prize by now. "Absolutely. We don't lobby for these prizes the way Americans do. Canadians are rather understated. We don't blow our horns."

After he left stem-cell research, Till became fascinated with improving the quality of life for cancer survivors.

"I wanted to do high-quality, rigorous research on subjective phenomena such as pain. That matters in medical decision-making. I cannot measure your pain with some gauge. I have to ask you questions. Are you in pain? What kind of pain? By being very rigorous, you can quantify subjective experience as rigorously as you can measure temperature."

More recently, Till has devoted his energies to making the publication of medical journals more widely available online.

As for McCulloch, he says he "never strayed very far, intellectually or professionally. I'm still an experimental hematologist."

Both men, who were inducted into the Canadian Medical Hall of Fame last year, are semi-retired professors emeriti at the University of Toronto, where they were given honorary degrees last spring to commemorate their outstanding careers. While their academic and professional lives have been less entwined over the past years, the bond they forged almost 50 years ago is still strong. "One of the things I'm happiest about," said McCulloch, "is that even now, all these years later, we're very good friends."

As for the possibility of winning the Nobel Prize, neither Till nor McCulloch is counting on it - or worrying about it.

"I think it's most unlikely, just because the discovery was so long ago," McCulloch said.

"Besides, winning the Nobel Prize was not part of our objective."

Were it to happen, Till said he would have similar feelings about the Nobel as he has about the Lasker. "It would be great for science in Canada in general and stem-cell science in particular. Because the field has been quite controversial, it hasn't had that much recognition. My hope is that it will get a lot more. I'm hoping we're the beginning of a trend where this kind of research that has great basic significance is recognized."

But neither he nor McCulloch cares a whit about glory.

"I actually think those who seek celebrity risk compromising themselves in terms of the quality of the science," said Till. "It's very tough to produce creative work on schedule, and that's what you have to do to maintain your celebrity status. That kind of game is not for me. It never was."

Joe Sornberger is an Ottawa-based writer specializing in health and science issues.