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Remembering cancer research pioneer

01 January 2011

Dr Ernest McCullochJanuary 2011 – Dr Ernest McCulloch, one of the fathers of stem cell research, has passed away. Along with his research partner Dr James Till, Dr McCulloch was the first discover that all blood cells come from certain stem cells in the bone marrow. Their discovery led to the development of bone marrow transplantation as a life-saving treatment for many cancers and became the foundation for promising stem cell research that continues today.

Read more about their discovery that led to the birth of stem cell research:

It all started with a few lowly lumps observed under a microscope one Sunday afternoon in 1960.

"They were just lumps," says Dr Ernest McCulloch, the man behind the microscope. "They didn’t have any particular characteristics that would identify them as being anything other than that."

But Dr McCulloch, then a young researcher at the Ontario Cancer Institute (OCI) had an idea. Could the lumps – observed in the tissue of mice that had received bone marrow transplants – be clusters of newly formed cells? He quickly began counting. The number of lumps rose in direct relationship to the number of marrow cells injected.

First thing Monday morning, he shared his findings with colleague James Till. "I remember walking down the hall and seeing Dr McCulloch coming at me waving this piece of graph paper and saying ‘I think you’ll find this interesting’. Which I did," Dr Till recalls with a chuckle.

The two men had very different backgrounds – Dr Till was a physicist, Dr McCulloch a physician – but they shared a commitment to rigorous science. "We trusted each other," says Dr Till. "We respected each other’s abilities and differences."

"We were both pretty well novices," adds Dr McCulloch. 

Working with graduate student Andy Becker, the two "novices" designed a series of groundbreaking experiments funded by the National Cancer Institute of Canada. Those experiments proved – for the first time ever – that a single cell could generate colonies of different cell types.

They had uncovered the power of stem cells. And in doing so, they changed the course of cancer research forever.

How they did it

Scientists had been theorizing about the existence of stem cells since the 19th century. But these potent cells are extremely rare and look no different than other cells, making them elusive research subjects.

Drs Till and McCulloch succeeded by coming up with a new search method. "The hematology of the day was based on recognizing cells on the basis of their microscopic appearance," Dr McCulloch explains. "We changed that into a methodology that depended on the function of the cells and on counting their progeny."

Researcher Dr Connie Eaves compares it to identifying a grandmother by the number of children and grandchildren she has created. "They came up with the idea to identify stem cells retrospectively – based on what the cells did," says Dr Eaves, a stem cell researcher and director of the Terry Fox Laboratory in Vancouver.

By providing a new analytical approach – and by advancing the idea of a hierarchy of cells based on function – Drs Till and McCulloch laid the groundwork for generations of researchers to come.

"They established the modern era of stem cell research," says Dr John Dick, another leading Canadian stem cell researcher. "The principles they developed are fundamental to everything we’ve done since."

The next generation

For 22 years, Drs Till and McCulloch continued their successful collaboration, publishing seminal papers and producing research that helped advance the field of bone marrow transplantation as a life-saving treatment for leukemia patients. And the NCIC continued to support their work with more than $18 million in funding.

Along the way, a stream of talented students passed through their OCI laboratory. Many have become internationally renowned researchers applying their stem cell knowledge to the fight against cancer.

"Till and McCulloch really launched this as a huge area of activity," says Dr Eaves, who did postdoctoral training there. "Their brilliance attracted strong and creative people to work with them and train under them."

"They were able to transfer a whole school of thinking that continues to emanate across the country," adds Dr Dick, now a Canada Research Chair in Stem Cell Biology and senior scientist at Toronto's University Health Network.

Today, this next generation of Canadian scientists is at the forefront of a research revolution that is changing our understanding of how cancer grows and how it can best be treated.

Hope for the future

Dr John Dick sparked this revolution in 1994 when he isolated the first cancer stem cell, and showed that these rare cells cause leukemia to grow in mice.

"John Dick’s pioneering work brought the initial work of Till and McCulloch into the current research field," says Dr Peter Dirks, a scientist and neurosurgeon at Toronto's Hospital for Sick Children. "He definitively demonstrated the presence of cancer stem cells."

In 2004, it was Dr Dirks’ turn to make headlines when he discovered cancer-causing stem cells in the brain tumours of mice. These cells have since been identified in prostate, breast and colon cancers. Says Dr. Dirks, "It looks like an increasing number of important and aggressive cancers are organized in this stem cell way."

The idea – gaining ever wider acceptance – is that a tiny number of cancer stem cells cause cancers to grow. They lie in wait, resisting treatment and then spawning a new round of malignant offspring. This would explain the high rates of recurrence in some cancers. 

Researchers like Dr Dirks are now searching for new drug agents that kill cancer stem cells. "It gives us hope for the future because we can identify these cells – and this in turn gives us hope to find new targets for treatment."

As for Drs Till and McCulloch, they remain modest about their contributions to this burgeoning field of research. "There’s still a lot of work to be done at the fundamental level on the role of stem cells in cancer," says Dr Till.

Dr McCulloch adds, "I’m just glad the work we did has proved over the years to have some clinical benefit."

More than 40 years after that fateful Sunday in the lab, the two Canadian pioneers are finally gaining the recognition they deserve. In 2004, they were inducted into the Canadian Medical Hall of Fame. In 2005, they received the Lasker Award, one of the world’s most prestigious medical research prizes.

As the venerable Lasker Foundation noted: "Like the stem cells they discovered, Till and McCulloch’s work has differentiated and matured in many different directions." And that has made the future of cancer research much brighter.