Stem cell science's new breakthrough

Toronto scientist Dr. Andras Nagy is suddenly trying to juggle some new demands on his time. He and his team recently made a breakthrough in stem cell research that has generated international attention.

It's a coup for the former mathematics whiz, who arrived from Budapest as a visiting scientist 20 years ago. He's now a senior scientist at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital, and he's excited by the work he's done.

"It's a leap toward deriving cells that will be safer to use in a clinical application," he says.

That's a rather dry way of describing a process that could eventually cure devastating maladies such as spinal cord injuries, Parkinson's disease or diabetes, to name a few.

What Nagy and his team did was to turn adult humanskin cellsinto embryonic-like stem cells.

How it works

The researchers inserted four genes into a chromosome via a string of mobile DNA, known as the "piggyBac transposon" system. The genes triggered a reaction in the cells that caused them to revert to an embryonic-like state. Then the genes were removed because they are powerful enough to cause cancer if they're left in the cell.

The development has several advantages. No human embryos were involved, so the process sidestepped the ethical debate that dogs the science around stem cell research. Also, using personalized cells means there is no threat of immune rejection, and this reprogramming method means there can be a ready supply of personalized cells for research.

Crucial contributions

The discovery further cements Ontario's reputation as a leader in stem cell research and regenerative medicine, and the technique is expected to see quick adoption by labs around the world.

Still, Nagy says his own breakthrough would not have been possible without the groundbreaking discovery by a maverick Japanese scientist in 2006. It was Shinya Yaminaka who proved that only four particular genes were required to create what are called induced pluripotent stem (iPS) cells. On March 31, Dr. Yamanaka was named a winner of the 2009 Canada Gairdner Awards for medical research, sometimes referred to as a "Baby Nobel"because several dozen winners over the years have gone on to receive a Nobel Prize for their research.

"It's very amusing, what happened in the last three years," says Nagy. "Probably just one person on Earth believed that just a few factors, genes, can rebirth our skin cells, making it into an embryonic [-like] stem cell. It was a big, big surprise to us, including myself."

Yaminaka's discovery also sidestepped the debate over using human embryos by using adult cells. His breakthrough had a serious problem, however: The virus he used to deliver the genes into the cell could cause cancer.

His work touched off an international race among scientists to see who would be the first to find a safe way to deliver the necessary genes and safely generate stem cells.

Nagy believes he had an advantage. In 2005, his lab created the first two Canadian human embryonic stem cell lines, learning a lot from the process.

Fast-forward to January 2008, when he had his eureka moment at a conference just outside Munich. "One of the talks was about a transposon system for totally different things, showing how efficient it is to deliver genes into a cell. I was listening to this talk and it clicked, that this is what we should [use to] try to deliver the stem genes into the cell."

"After the talk, I went for lunch with the speaker. I grabbed him, and during lunch, I showed him, 'I've got this idea here, so why don't we collaborate,' and we tried this system in reprogramming a cell," Nagy said.

"This is the birth of the idea at the lunch table," he says, holding up a coffee-stained menu with notes and diagrams scribbled across it. "I still have this disgusting thing," he says, laughing. "When I came back to the labs, I told the guys, let's go for it."

In April Nagy's research was further boosted after meeting stem cell researcher Keisuke Kaji at the University of Edinburgh. He discovered Kaji's British team was also working on the same project. Kaji had developed a novel way of stringing the four genes together to insert them into the cell and extract them in one go, instead of fishing around for four separate genes, but Kaji didn't have transposon. So the two agreed to collaborate. It is was these two separate elements that made the project such a success, but Nagy describes this "big leap" as a bit of a "poker game" or "psychological warfare."

"It's a very fast field," he said. "So there's always the chance someone else is working on the same thing."

The trick was to get published before anybody else and he wanted a review in the most prestigious journal, Nature.

After working and documenting for an entire nerve-wracking year, Nagy submitted his paper on Dec. 23, 2008, while his team partied in the lab. On March 1, 2009, it was published online in Nature.

Canada's collaborative culture

Nagy's discovery builds on a solid history of stem cell research and regenerative medicine around the University of Toronto and McMaster University in Hamilton. Stem cells and cancer stem cells were also discovered in Toronto.

He praises his own team for their work and enthusiasm, but he says the collaborative culture in Toronto helped him survive in an intensely competitive field.

"In Toronto, we have a different philosophy of doing science than in other places, so we work together as a large team or family so we share, we communicate before publication.

"We are totally an open lab concept, this downtown area of Toronto. We have a regular get-together, bi-monthly stem cell meetings with more than a hundred people coming together where we share openly what we have. Maybe our resources are not as good as Harvard, but we can compensate for this with intensity and openness."

All the same, he says, Canada's research would move along more quickly if the federal government would give scientists more money. He hopes the loosening of restrictions on federal financing in the U.S. for stem cell research will impress Ottawa.

"Hopefully they will recognize the importance of this field," says Nagy. "I think medicine and medical care is a good investment for a society."

For instance, Nagy says, Canada spends about $12 billion a year on problems associated with diabetes, and he thinks a cure for it would be a smart investment. He's hoping his own lab will move toward research to treat diabetes.

His immediate priority, though, is to see his experiment duplicated on human cells.

In the meantime, scientists in California are about to begin the first human stem cell trials to try to repair spinal cord injury. Much is riding on the experiment. People aren't expecting sudden miracles, but they will be looking for evidence that the hype will one day live up to the hope.