The Big Promise of a Tiny Cell

After almost half a century of research, U of T scientists believe they may be on the verge of making exciting discoveries about stem cells that could lead to new treatments for a wide range of conditions, from heart disease to multiple sclerosis. Consider in the not-too-distant future:

You’ve been blind in one eye since being hit in the face with a baseball when you were a kid. But doctors take cells from the cornea of your good eye, isolate the stem cells, multiply them in the lab and transplant them into the damaged eye. Your sight is restored.

Or how about this: your mother has Parkinson’s disease, the degenerative disorder of the nervous system involving a lack of the brain chemical dopamine. In a non-invasive procedure, doctors take a small sample of cells from her skin and reprogram its stem cells in the lab; instead of growing into more skin cells, they grow into brain cells. At this point, drugs can easily be tested on the new cells in the lab to see which medication will be the safest and most effective for your mother.

Or this: your son has developed Type I diabetes and his body no longer produces insulin. Instead of saddling him with daily needles or a pump, specialists take a bit of his skin, coax its stem cells into becoming insulin-producing cells and then transplant them into your son. Since the new transplanted cells were made from his own cells, there’s no risk of his body rejecting the new tissue.

It’s called personalized stem cell medicine, and it’s currently one of the hottest fields of medical research. Advances are coming so quickly that the above scenarios could become reality this decade. In fact, stem cells are already being used in clinical trials to cure certain forms of blindness. According to the results of one trial, published in the American medical journal Stem Cells in December, eight patients in the United Kingdom who were blind in one eye have at least partially regained their vision. Drug testing on tissue grown in labs from skin cells is expected to begin within two or three years. This will reduce negative side-effects in patients, since drugs can be tested on patients’ tissue in labs and not on the patients themselves. Growing spare parts for transplant, such as hip or knee cartilage or even patches for a lung, kidney or heart, from a patient’s own cells may be possible farther in the future.

The implications are staggering: “This field of research is exploding,” says Janet Rossant, an internationally recognized developmental biologist known for her pioneering stem cell research in mice, and a professor in U of T’s department of molecular genetics. “It’s going to be quite revolutionary in the way we think about human disease, allowing us new ways to understand disease but also new ways to develop and deliver therapies.” The potential of stem cell medicine could ultimately touch any condition where cells have been damaged through disease or injury. This could include many types of heart disease, cancer, spinal cord injury, Type I and II diabetes, blindness, cystic fibrosis, multiple sclerosis, liver and kidney disease, Parkinson’s, Alzheimer’s and many more.

Among the major stem cell research centres in the world, Canada ranks near the top, with the University of Toronto holding a prominent position. Not only is there a critical mass of at least 70 stem cell scientists and principal investigators now working in the field in Toronto alone, but there’s a unique spirit of collaboration among researchers and across institutions in Ontario, which helps attract both talent and funding. British-born Rossant is the director of the newly launched Ontario Initiative in Personalized Stem Cell Medicine, which brings together researchers from U of T and five other institutions: the Hospital for Sick Children, the Samuel Lunenfeld Research Institute at Mount Sinai Hospital, the McEwen Centre for Regenerative Medicine (all in Toronto), and research centres at McMaster University in Hamilton, and the University of Ottawa.

In 2009 the group received $25 million from provincial and federal governments and private sources. The money will go chiefly to purchase equipment to study cell behaviour. The six Ontario centres will also collaborate with institutes in Kyoto, Japan, and San Francisco. Because the field is so complex, collaboration is vital, says Rossant, who is also the chief of research at the Hospital for Sick Children and a senior scientist in its developmental stem cell biology program. “We have to exchange information so we can learn from each other and really be able to move the field forward.”

Stem cells are among the body’s most flexible cells. These wondrous little powerhouses have two unique qualities: they can make infinite copies of themselves; and they can give rise to a specialized cell type, such as a muscle cell or a red blood cell. Their main role seems to be to repair and renew the body’s tissues.

Embryonic stem cells appear to have the greatest flexibility of all stem cells; they can become any one of the 200-plus cell types in the human body. Adult stem cells, which have moved beyond the embryonic stage, have a more limited range of options, usually restricted to the tissue in which they reside.

Two U of T researchers – physicist James Till and biologist Ernest McCulloch, working together at the Ontario Cancer Institute – discovered the existence of stem cells in the early 1960s. Their groundbreaking work helped pave the way for the very first stem cell therapy – bone marrow transplants, which have been performed for more than 40 years in patients with blood diseases such as leukemia and aplastic anemia. The stem cells in the healthy, transplanted bone marrow are capable of growing a whole new blood system for the recipient.

In 1998, researchers at the University of Wisconsin became the first to isolate embryonic stem cells in humans and grow them in the lab. These embryonic stem cells were derived from very early embryos just a few days old and no bigger than the period at the end of this sentence. However, research on human embryos was controversial from the beginning. The embryos, given for research purposes with the donors’ consent, were developed from eggs fertilized in vitro at fertility clinics, and would otherwise have been discarded. But pro-life groups vehemently opposed the practice, and many others were never completely comfortable with the idea of experimenting on human embryos. Former U.S. president George W. Bush banned new funding of such research, and there was much public debate about the ethical issues.

Then in 2006, Japanese researcher Shinya Yamanaka discovered what has been called an example of modern-day alchemy – a way to take adult stem cells from a mouse and get them to revert to embryonic stem cells. A year later, in 2007, he did the same with human stem cells, taking a bit of skin from a 36-year-old woman and, by adding just four genes, coaxing the adult stem cells to turn back the clock and become like embryonic stem cells. These new cells were called induced pluripotent stem cells, or iPS cells. Stem cell researchers around the world were giddy at the news that it was now possible to take cells from any human and turn them into embryo-like cells that could be studied in the Petri dish. Some researchers think that the discovery could eventually eliminate the need to use human embryos at all. “Embryonic stem cell lines are still very important to study because they’re the gold standard,” says Rossant. “But as we go forward there’s no question that everybody has really jumped onto this concept of being able to take adult cells and turn them back.”

Yamanaka, who first made the discovery, now chairs the Ontario initiative’s external advisory board, a move seen as top-level endorsement of Canadian research. Not only was Yamanaka attracted by the high quality of talent here, but he realized that Toronto’s ethnic diversity would ultimately offer a broad range of patient samples for testing new drugs and other therapies.

But there was a potential problem in reverting these iPS cells. To transfer the necessary four genes into the adult stem cell, researchers had to use viruses, which successfully reprogrammed the cell but also left behind DNA material that could create mutations, such as triggering the genes to become cancerous. Clearly, this method was far too risky ever to use in humans. But early in 2009, a U of T professor discovered a safer method to deliver the genes without using viruses – and made global headlines in the process. Andras Nagy, a senior scientist at Mount Sinai Hospital and a professor in molecular genetics at U of T, had a brainwave while attending a conference in Germany and grabbed the nearest piece of paper – it happened to be a lunch menu – to scribble down the circles, arrows and abbreviated words that would become the biggest stem cell breakthrough of the year.

Instead of using a virus, Nagy’s hastily jotted idea was to insert the genes into a tiny piece of DNA called a jumping gene, which he nicknamed “piggyBac.” Once it had done its job of ferrying the four genes into the cell, the jumping gene could be removed, leaving no trace. Back home, his lab tried the method at the first opportunity. “It was a surprisingly simple idea that no one had tried before – and it worked,” says Nagy, whose desk still bears the propitious, coffee-stained menu. In collaboration with a U.K. group that was on the same track, Nagy published his finding last year to worldwide acclaim. In June he became the only Canadian named to Scientific American’s Top 10 Honor Roll, among such luminaries as Barack Obama and Bill Gates.

Nagy reprogrammed his lab, too, so that it’s now heavily focused on this area of research. “We are still very, very excited about it,” he says. “We expect that in certain cases of blindness, diabetes and spinal cord injury, cell replacement could be used – and relatively soon.” Nagy, originally from Hungary and invited 20 years ago by Rossant to come and work in Canada, is proud to be part of the stem cell research community here. “Honestly, I’ve never seen such a high level of stem cell laboratories anywhere else in the world. And our attitude here is different. We like to talk to each other, which makes our collaborative community very unique.”

Another rare feature among researchers in Canada is the diversity of disciplines: developmental biologists work alongside geneticists, clinicians and even engineers, each contributing a piece of the puzzle. For instance, bioengineer Peter Zandstra, a U of T professor of tissue engineering, has designed marvels of technology – bioreactors that take a few stem cells and, by controlling their environment, significantly increase their numbers. In the short term, this would provide larger sources for testing, with the hope of developing better drugs more quickly. In the longer term, it would ideally supply enough stem cells to replace bone marrow transplants for every patient who needed one, or enough insulin-producing cells for every diabetic.

Like many stem cell scientists in Canada, Zandstra is an academic “grandchild” of the original U of T discoverers of stem cells; he was trained by someone who was trained by Till. “This field is incredibly exciting,” says Zandstra, who is also the Canada Research Chair in Stem Cell Bioengineering.

“Things we didn’t think were possible five years ago we can now do routinely in the lab.”

Many of these astonishing accomplishments have begun in Canadian labs. For decades scientists had thought that any cell was capable of causing cancer, until McEwen Centre scientist and molecular genetics professor John Dick in the mid-1990s became the first to discover the existence of cancer stem cells. These are abnormal stem cells that resist chemotherapy and have been shown to cause cancers of the breast, prostate, colon, blood and bone. More recently, Freda Miller, a professor of molecular genetics and a senior scientist at Sick Kids, was one of the first to show that stem cells could be harvested from adult human skin. She’s now researching how skin-generated neural stem cells could help repair spinal-cord injuries and help people with cognitive dysfunction, such as learning disabilities and autism. Fellow U of T professor and McEwen scientist Derek van der Kooy has done groundbreaking work on retinal stem cell therapy, which may have implications for age-related macular degeneration, the vision-robbing condition that affects an estimated one million Canadians.

Another busy lab is Gordon Keller’s. (In 2005, shortly before Keller returned to Canada after working for 16 years in the U.S., New York magazine named him one of the six doctors New York couldn’t afford to lose.) He’s the director of the McEwen Centre and a U of T professor of medical biophysics, and his Toronto lab was the first in the world to identify cardiac progenitor cells from human embryonic stem cells. Seen through a microscope, the tiny, colourless clusters of 1,000 to 2,000 beating cardiac cells pulse away in a Petri dish. Elsewhere in the lab, you can also see red blood cells that have been grown from stem cells, as well as clusters of liver cells and insulin-producing cells. Will stem cell transplantation save lives? “Absolutely,” Keller says. “We predict that transplanting insulin-producing cells in diabetics will be one of the first success stories.” But he cautions that there are still a lot of unknowns. “For example, the cells we’ve generated that secrete insulin do not sense glucose very well.” He adds that we still need to conduct basic research to determine exactly how a human embryo makes insulin- secreting cells so that when we mimic this process in the lab, we don’t miss any steps. The lab-produced cells need to share every property of the “natural” cells, including the ability to sense glucose well.

And that’s where Rossant’s research comes in. For 30 years she’s been working on understanding the exact sequence of steps that makes a fertilized egg grow into an entire, complex human being. “We’re actually quite good at making some of those early developmental events occur in the Petri dish,” she says. “But the challenge we’re facing now is getting them to the end of the process.” Researchers have to keep going back to the embryo – in Rossant’s case, mouse embryos – to follow the precise pathways of development.

There are other challenges, too, such as ensuring that any cell therapy is safe for the patient. Rossant worries about the rise of stem cell tourism, where desperate patients travel to other countries to seek out untested therapies. She says that in most cases the transplanted stem cells don’t survive long, and in at least one case an experimental stem cell treatment caused new tumours in the patient. “These are powerful cells,” she warns.

There are other ethical issues besides the use of embryos. For instance, what rights would donors have to the skin they donate for research, or any organs that have been developed from it? Also, since iPS cells have the potential to create human eggs and sperm, what would happen to those? Who would own them? Most experts agree that while regulations by Health Canada will ultimately be necessary, we’re not at the stage yet where we can foresee all the issues that might arise. We don’t yet fully know the power of stem cells.

As Rossant says, “The good thing about these wonderful cells is they can make every cell type,” adding wryly, “And the bad thing about these wonderful cells is they can make every cell type.” Only by observing every step of their transformation and carefully emulating them in the lab will researchers be able to harness the mysterious power of stem cells. “We haven’t solved it yet,” Rossant says. “But we’re close.”

Marcia Kaye (marciakaye.com) of Aurora, Ontario, is an award-winning magazine journalist specializing in health issues. She wrote about the science of sleep in the Spring 2009 issue.