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Dr. Ernest McCulloch dies at 84; he and research partner were first to isolate and identify a stem cell

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Dr. Ernest McCulloch, who with biophysicist James E. Till was the first to isolate and identify a stem cell, opening the door immediately to bone marrow transplants and eventually to what researchers believe will be a host of treatments for a broad spectrum of diseases ranging from spinal cord injuries to Alzheimer's, died Jan. 20 in Toronto, just two weeks shy of the 50th anniversary of the publication of the pair's seminal discovery. He was 84.

"It's impossible to overstate the enormity of Till's and McCulloch's discovery and longtime collaboration," Dr. Christopher Paige of the Ontario Cancer Institute, where the pair worked, said in a statement. "Their work changed the course of cancer research and lit the way to what we now call regenerative medicine — the use of stem cells for bone marrow transplants and many other types of disease research."

Stem cells come in two types, embryonic and adult. Embryonic stem cells have the potential to turn into any type of cell in the body if exposed to the right stimuli, a process called differentiation. Adult stem cells have already gone partway down the path of differentiation, and thus can only turn into a few types of related cells. Stem cells in the bone marrow, for example, can only turn into blood cells.

Researchers had speculated about the existence of stem cells since the beginning of the 20th century, but the reality had never been confirmed and no one had ever seen one before the Canadian pair began their work.

McCulloch and Till were young researchers who had just joined the Ontario Cancer Institute at Princess Margaret Hospital at the height of the Cold War in the 1950s when they decided to study the effects of ionizing radiation on mice. Their purpose was twofold: to learn how exposure to radiation from nuclear weapons killed and to study how radiation destroyed tumors.

Their discovery of stem cells, McCulloch later said, was "accidental."

The researchers irradiated mice with enough X-rays to kill the animals within 30 days if they did not receive a transplant of fresh, undamaged bone marrow cells. The researchers then injected varying amounts of cells to determine how many cells were necessary to keep the animals alive.

On a Sunday morning 10 days after injecting the cells, McCulloch observed nodules in the spleens of the surviving mice. McCulloch wasn't the first to see these nodules, Till later said, but he was the first to grasp their importance. With a background in bacteriology, McCullough suspected the blood cells were forming the equivalent of a bacterial colony and that this was the source of the new blood cells that were keeping the animals alive.

The pair published their observation in 1961 in a largely ignored paper in the obscure journal Radiation Research. It took them two more years of intensive research before they definitively proved that all three types of blood cells — red cells, white cells and platelets — were produced by a single stem cell. That paper made it into the journal Nature.

"Without their work, we would never have had bone marrow transplants," Dr. Michael Rudnicki, scientific director of the Stem Cell Network, told the Toronto Star. "We might have muddled our way through it ... but their work provided the theoretical underpinnings for bone marrow transplant as a therapy, which has been in the clinic now for 40 years and has saved countless lives."

Till and McCulloch were a study in contrasts. McCulloch came from a well-to-do Toronto family: His father and uncles were all doctors and he attended Upper Canada College, a private high school in Toronto, before proceeding directly to medical school at the University of Toronto. Short and stocky, he wore rumpled tweeds and cardigans that were often covered with chalk dust from the ever-present tool that he frequently held in his mouth.

In contrast, Till was tall, lean and immaculately tailored, a whip-smart prairie boy from Saskatchewan who earned scholarships that brought him a Yale doctorate in biophysics. But they worked together remarkably well. They agreed they would alternate being the lead author of papers so there would be no arguments about priority for research.

"I remember him saying: 'When we disagreed, we knew the right answer was something else,'" Till said. After McCulloch's funeral, Till said: "I've lost a supportive and steadfast friend."

The pair won the 2005 Albert Lasker Award, a major U.S. medical prize that is widely considered a precursor of the Nobel Prize in medicine. They frequently had been rumored to be on the short list of nominees for the Nobel. Many experts think they should have won it, but it is now too late because the prize is never awarded posthumously.

Ernest Armstrong McCulloch was born April 27, 1926, in Toronto. He is survived by his wife, Ona; four sons, James, Michael, Robert and Paul; a daughter, Cecelia E. MacIntyre; a sister, Tot Johnson; six grandchildren; and one great-grandson.

thomas.maugh@latimes.com

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