How to reboot the human body

In Toronto, a network of researchers work with the building blocks of human life to do the impossible

Sitting in his sunlit office in downtown Toronto, renowned geneticist Andras Nagy clicks through a computer slide show. The images show various people: different ages, different shapes and sizes. “This person has diabetes,” he says, gazing at the screen. “She needs insulin producer cells in her body.” He clicks to the next slide. “This person has multiple sclerosis. He needs myelin,” which insulates the nerves. Another: “This person had a tumour on his spine, which was removed,” but the resulting spinal cord injury left the patient with a disability.

“This is where the field of stem cells is promising,” says Nagy, looking up from the screen. With an unlimited source of the missing cells, “we could cure the disease.” Today, as senior investigator at Mount Sinai Hospital’s Samuel Lunenfeld Research Institute, Nagy is one of a handful of superstar researchers working to finally bring stem cells out of the lab, and into the clinic. Every day, they’re using the building blocks of human life to do what was once thought impossible. But doing the impossible is not exactly new for Nagy.

Over a decade ago, Nagy succeeded in creating an entire mouse from stem cells, proving they can change into virtually any cell type in the body. “No mother, no father. Just the petri dish,” says Nagy. In 2005, he established Canada’s first stem cell lines from human embryos. Now they’re focusing on a new area of research—one that suggests it may be possible to “reboot” human cells, creating heart cells or neurons out of skin. “We’re moving faster than everyone thought possible,” says Michael Rudnicki, scientific director of Canada’s Stem Cell Network, which connects more than 80 leading experts across the country.

For the millions around the world suffering with chronic disease, they can’t move nearly fast enough.

For decades, scientists have known that, in their embryonic form, stem cells can morph into any cell type in the body. Last year, Kyoto University’s Shinya Yamanaka made a startling announcement: it also works the other way round. Working with human skin cells, Yamanaka found a way to push cells backwards, to an embryonic-like state. These induced pluripotent stem cells (IPS cells for short) offer a way to treat patients with their own body’s cells. “It enabled us to overcome the barrier of having relatively few embryonic stem cell lines,” says Gordon Keller, director of the McEwen Centre for Regenerative Medicine in Toronto. “Suddenly, we can make cells directly from the patient.”

Imagine treating a car accident victim for a broken back, and injecting her own cells into the spine to speed recovery. Or giving drugs to a stroke patient that harness his stem cells to stimulate repair. One day, “you will probably be able to buy a reprogramming kit from a company,” Keller suggests. It sounds too incredible to be true, and for now, it is.

For one thing, IPS cell therapy would be expensive and time consuming: turning an adult cell into a stem cell, then into a new cell type, currently takes about three to four months, Nagy says. When a car accident victim gets rushed into hospital, doctors don’t have that kind of time. And compared with embryonic stem cells, IPS cells are still not entirely understood. “The biggest challenge is differentiating stem cells into a stable, safe form,” says Janet Rossant, chief of research at Toronto’s Hospital for Sick Children (SickKids).

Above all, experts warn, tinkering with the human genome could be dangerous. To create an IPS cell, Yamanaka isolated four genes that are active in embryonic stem cells, but dormant in adult ones (humans have an estimated 30,000 genes). He then used a virus to push these four genes into the adult cell, forcing it to reboot. The risks involved are unclear. Virus insertion is totally random: it could ding up other genes along the way, creating rogue cells, mutation and even cancer. “The virus method is not safe,” Nagy says. “We have to find a way to reprogram without genetic change.”

That’s what Nagy’s attempting to do. He’s on the verge of publishing research detailing a “non-viral system” to create IPS cells.

“This is a totally new way,” he says. “We think it’s going to change how they do it globally.”

Just a few short blocks from Mount Sinai Hospital, Aaron Cheung, a University of Toronto graduate student working in the James Ellis lab at SickKids, peers down a microscope and into a petri dish. It contains a scattering of small, nondescript grey lumps: clusters of IPS cells. These were created, Cheung says, with a skin sample taken from a patient with Rett syndrome, a childhood neurodevelopmental disorder affecting about one in 10,000 baby girls. “It’s one of the leading causes of mental retardation in females,” Cheung says. “That’s why we’re very interested in it.” If these IPS cells can be turned into neurons, they could provide a unique window on the condition, and perhaps even a step toward a cure.

Until now, creating an animal model was often the best way to study a disease. Yet this method has obvious limitations—after all, a mouse is not a person. “In mice, you can’t model higher function, like cognitive abilities,” Cheung says. IPS cells give researchers an unprecedented tool with which to understand the human body. “We can’t take patients with Rett syndrome and harvest their neurons,” says Cheryle Séguin, a post-doctoral research fellow in Janet Rossant’s lab. “Having access to these cells lets us do experiments that otherwise wouldn’t be possible.”

The impact it could have on drug research may be equally profound. “Drug metabolism occurs in your liver, and liver cells are something we can now readily make,” Séguin says. “You could do a lot of your drug testing in the dish, instead of in people.”

Although clinical use of IPS cells is a long way off, “research grade” cells are already being stockpiled. Toronto is now home to the Ontario IPS Cell Facility, the first centre of its kind (Séguin is acting manager; Nagy sits on its advisory board). Located at SickKids, the facility opened in June; since then, it has banked 20 cell lines, including Cheung’s. At the request of Ontario scientists, these will be turned into IPS cells and provided by the bank at cost.

In the same blue-glass tower that houses the Ontario IPS Cell Facility—in fact, just a few floors down—is the McEwen Centre for Regenerative Medicine, devoted to a relatively new type of medicine that aims to repair or replace living tissues and organs. Keller, its director, made headlines in April after successfully growing human heart progenitor cells, a crude form of heart cell, from embryonic stem cells. (These progenitor cells can make human heart cells that actually pulse, like a miniature human heart.) There, researchers have “set up a companion facility to the IPS generating facility,” Keller explains. Just as the team upstairs specializes in creating IPS cells, Keller’s can shape them into a final product. “Since we have the expertise, it’s best for us to make cells for people who study them,” he says.

It is unusual, in the competitive arena of stem cells, for two facilities like the IPS Cell Facility and the McEwen Centre to collaborate. Yet it’s this kind of co-operation that helped make Toronto the birthplace of stem cell research: it was here that Ernest McCulloch and James Till discovered so-called “seed cells” over 40 years ago. “They trained a legion of students, who went on to train more,” says Rudnicki of the Stem Cell Network. Founded in 2001, it was the first network of its kind in the world.

Today, Toronto’s Discovery District—several city blocks encompassing the University of Toronto and its affiliated hospitals, Mount Sinai and SickKids—brings together thousands of researchers working in every imaginable discipline. It’s home to the MaRS Centre,
a science and business hub where lab technicians rub shoulders with patent lawyers, investors and biotech entrepreneurs. “Everything is a five-minute walk away,” says Nagy, who can point to some of his collaborators’ offices out his office window.

Ontario has been eager to support the stem cell industry, kicking in $1 million for the IPS Cell Facility (the SickKids Foundation also provided money), part of its $3-billion innovation agenda. “Our researchers are an essential precondition to prosperity in the 21st century,” says John Wilkinson, Ontario’s minister of research and innovation. All this has made Toronto a magnet for stem cell scientists from around the world, says Keller, a Saskatchewan native who left a job in New York to take the reins at the McEwen Centre (New York magazine called him a medical mind that the city couldn’t afford to lose). In 1988, Nagy left his home in Budapest to take a research job in Toronto. He’s been here ever since.

The spirit of collaboration has spread beyond provincial borders. Nagy and other University of Toronto scientists recently travelled to Japan to forge a research-sharing pact with Kyoto University’s team, including Shinya Yamanaka, who discovered IPS cells. U of T and SickKids have also partnered with California’s Gladstone Institute of Cardiovascular Disease, a stem cell centre where Yamanaka has another office. (Ontario and California account for 70 per cent of all North American stem cell research.)

But collaboration can only go so far. Driven by an aging population, regenerative medicine is set to become big business: it could be a $500-billion opportunity worldwide by 2010, notes a MaRS industry briefing. As of last year, over 500 companies were dipping their toes into cell therapy. In 2005, the Stem Cell Network and its academic partners created Aggregate Therapeutics Inc., a company aimed at getting Canadian stem cell technologies to market (it’s now managed by MaRS). “The commercialization of stem cell science is still in a very early stage,” says Ilse Treurnicht, CEO of the MaRS Discovery District. “This field is going to transform medicine over the next 50 years.”

With so many world-class minds working toward a common goal, science is moving at an incredible pace. “In the last two years, it seems anything’s possible,” says Benoit Bruneau, associate investigator at the Gladstone Institute in San Francisco. Before the discovery of IPS cells, the work that’s now under way was “sort of pie in the sky,” he says. “I honestly didn’t see any of this coming.”

If the idea that a skin cell can morph into a stem cell is a mind-bender, here’s another: adult cells aren’t just able to move backwards, it seems. They might be able to go sideways, too. In August, a team of Harvard biologists announced they’d successfully changed one type of adult cell directly into another, inside a living mouse—without turning it into an IPS cell first. They flipped three molecular switches to convert a pancreas cell into an insulin-producing one, the kind that diabetics need.

It’s a notion that intrigues Andras Nagy. When an adult cell is reprogrammed into an IPS cell, and begins to move into an embryonic-like state, Nagy hypothesizes it hits a “point of no return”—a grey zone where it’s not quite an IPS cell, and not quite an adult cell either. This he calls “Area 51.” Unlike an IPS cell (which can become virtually any cell type), what falls inside Area 51 might be a bit more specialized: “Maybe they can make only blood, or only muscle,” he says. Because they’re already on the path to becoming adult cells, they might be more efficient to work with than IPS cells—so, when that car accident victim is rushed to hospital, these Area 51 cells can be more quickly and easily changed into the cell type that’s needed to help her.

“Most likely what will happen is a cell bank will be created,” Nagy says. Unlike those stored at Ontario’s IPS bank, though, Nagy believes these cells will be maintained in that in-between zone, Area 51. “They will be properly typed for compatibility, like organ transplantation,” he explains. “They will be ready on the shelf. When a doctor needs it, they must simply look for a match.”

Leaving his office, Nagy walks into the lab and takes a petri dish from the refrigerator. He places it under the microscope. What it contains is beautiful: elongated shapes that look delicate as frost. They quiver with movement. Nagy’s lab created these skeletal muscle fibres directly from skin, through an alchemy they’re now working to understand.

In our bid to extend human life, one thing is clear: the meaning of “life” is perhaps much more complicated than we ever imagined. “When you see cells just sitting there, it’s hard to believe they’re alive,” Nagy says. “When you see them actually moving in the petri dish, it is evident.”

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