A Living Legacy

A Living Legacy At the birthplace of stem cell research, the next generation of scientists continues to advance the field. In Toronto’s downtown Discovery District, world-class stem cell researchers populate the buildings like athletes at the Olympics. On University Avenue, Andras Nagy, a renowned innovator in induced pluripotent stem (iPS) cells, works at the Samuel Lunenfeld Research Institute, housed within the towering Mount Sinai Hospital. Across the street and two blocks north, within the gleaming Toronto Medical Discovery Tower, sits Janet Rossant, a famed developmental biologist at the Hospital for Sick Children and pioneer working with stem cells in the early embryo. Rossant shares a floor with James Ellis, codirector of the Ontario Human Induced Pluripotent Stem Cell Facility. Five floors below them are John Dick, discoverer of the first cancer stem cell, and Gordon Keller, director of the McEwen Centre for Regenerative Medicine, who in 2008 was the first to coax embryonic stem cells into three types of heart progenitor cells. And that’s just a few of them. Less than a mile from this hub of activity is Sherbourne Street, where in the early 1960s an unlikely pair, biologist Ernest McCulloch and biophysicist James Till, discovered the first stem cell. It was the inception of a revolutionary new field, and the first in a slew of discoveries that put Ontario on the forefront of stem cell research. As they explored some of the first mechanisms of stem cell activity, McCulloch and Till trained a generation of students and postdocs, who then spread out across Ontario. “They have a wonderful group of stem cell researchers,” says Leonard Zon, director of the stem cell program at Children’s Hospital Boston in Massachusetts. “There’s a lot of respect for them.” Today, that legacy has helped create a series of ongoing multidisciplinary projects, the seeds of an international consortium, and the largest stem cell gene expression database in the world—all based in Ontario. Stem cell research in Ontario is “as good as it gets,” says Kenneth Chien, head of the cardiovascular program at the Harvard Stem Cell Institute. The SCN helped create this vibrant and interactive community. The Network The Ontario stem cell locus is a tightly knit community with monthly stem cell meetings, weekly video conferences, and group grant applications—a veritable trading post of talents and resources. “It’s a vibrant and interactive community,” says Derek van der Kooy, a neural stem cell researcher at the University of Toronto. The community owes part of its collegial atmosphere to the Stem Cell Network (SCN), a national organization founded by the Canadian government in 2001 that today is more than 100 investigators strong and has received over $60 million in government funding. The network was the first of its kind. Before it existed, biologists, bioengineers, clinicians, and ethicists barely knew each other, recalls Michael Rudnicki, scientific director of the SCN and a muscle stem cell researcher. “We were strangers. Now, we are truly a national community,” he says. The network is invaluable, says Harold Atkins, medical director of regenerative medicine at the Ottawa Health Research Institute (OHRI) and a member of the SCN. “We have a lot of interaction and correspondence. It’s a very rich community.” In 2004, the SCN entered the international stage as the founding member of the International Consortium of Stem Cell Networks, a group of 19 stem cell networks stretched around the world. The organization has also spawned a regenerative medicine biotech company (Aggregate Therapeutics), a Cancer Stem Cell Consortium, and two research databases: StemGen and StemBase, the largest stem cell gene expression database in the world and an important part of the International Regulation Consortium (see The Big Ome for more on the IRC). A Strong Foundation It was not solely McCulloch and Till’s discovery or the area’s collegial nature that propelled this region to one of the top stem cell communities in the world. Ontario’s other research strengths, especially early embryonic development and bioengineering, have encouraged researchers to pursue innovative stem cell research projects. “We’re broad, strong and deep,” says Rudnicki. An extensive clinical infrastructure, with 60 hospitals in Toronto alone— including 12 research hospitals—has helped make the region a prime location for stem cell clinical trials. “The merging of the stem cell biology programs with their leading clinical care centers will continue to ensure their leadership in regenerative medicine,” says Harvard’s Chien. Some of the multidisciplinary projects in the region include: • Eye Repair: In 2000, van der Kooy isolated the first mouse retinal stem cells, demonstrating the surprising capacity of the mammalian eye to regrow. Since then, he and a team of investigators led by Valerie Wallace, a vision researcher at OHRI, continue to purify and characterize human retinal stem cells, designing methods to coax them into various eye cell types. “Right now, we can take these cells out of the human eye, grow them in a dish, and change them into photoreceptors,” says van der Kooy. In a complementary SCN-funded project, May Griffith of OHRI developed the first artificial cornea, which has completed a Phase I clinical trial. Mouse embryonic stem cells with flourescent marker • Multiple Sclerosis: Atkins, a bone marrow tranplant physician at OHRI, began working with neurologist Mark Friedman 12 years ago to develop a stem cell treatment for multiple sclerosis. Canadians have one of the highest rates of MS in the world. Over the last 8 years, the researchers have administered to 25 patients an experimental treatment in which high doses of chemotherapy are used to wipe out the immune system, which is then rebuilt with the patient’s own fresh bone marrow stem cells. Most patients have experienced no further deterioration, and some have even seen improvement. “For the right person with MS, I think it’s going to be an important treatment,” says Atkins. “It’s given us insight into how MS works and the capacity of the brain for plasticity and repair.” • Cancer Drug Testing: In 2005, a team of chemists, cell biologists, bioengineers, and clinicians led by John Hassell at McMaster University began to develop drug-screening assays for four cancer stem cell populations. Hassell and colleagues have already identified an inhibitor of breast tumor–initiating cells and are pursuing the discovery in partnership with Merck. • Skin-Derived Progenitor Cells: Last year, Freda Miller, a senior scientist at the Hospital for Sick Children, confirmed that skin-derived progenitor cells (SKPs), which her lab isolated from the skin of rodents and humans in 2006, are truly stem cells, capable of self-renewal and differentiation into both neural and mesodermal cell types. Miller and colleagues are now investigating the use of SKPs to treat spinal cord injury. A Change of Fate In 2009, a game-changing discovery brought the world’s attention to Ontario laboratories. Two years earlier, Shinya Yamanaka at Kyoto University demonstrated the remarkable feat that differentiation can be reversed. The introduction of four transcription factors through a viral vector can revert adult skin cells into an embryonic-like state, creating induced pluripotent stem cells, or iPS cells. Nagy, an ESC researcher at Lunenfeld, rapidly shifted his research focus to iPS cells, and after a serendipitous meeting with a young PI (see Pluri-Pioneer for a profile of Nagy), within a year he and his team published the next great innovation in iPS—reprogramming without the use of a virus, which could potentially damage a cell’s DNA. “He’s a technological guru,” says Zon. “He’s very good.” Since then, iPS has become a pillar of stem cell research in the region. “Ten years ago, if you were to tell someone you could take a terminally differentiated somatic cell and make it into an embryonic stem cell, they’d smack you upside the head and say you’re insane,” says Lynne-Marie Postovit, a researcher at the University of Western Ontario. “Now we’re understanding that you can, and it doesn’t even take that much to do it. In the next 10 years, we’ll be finding lots of new ways to understand stem cells and harness them.” In 2009, the Ontario government announced the Ontario Initiative in Personalized Stem Cell Medicine, a $10 million iPS-focused research project led by Rossant, which will unite 30 regional stem cell researchers to advance iPS technologies and develop health-care products. With so many researchers in the area working on overlapping projects, one of the benefits of the initiative is the chance to avoid the duplication of work. “It would be really discouraging to know that people 100 miles away were doing the same experiment,” says Mick Bhatia, director of McMaster University’s Stem Cell and Cancer Research Institute. “There is no reason not to share information at this point. There’s so much to do.” The initiative will emphasize translational research, developing intellectual property, and working with industry partners to commercialize products. A large part of the $10 million in funding will be used to train the next generation of stem cell researchers and staff, including more than 400 graduate students, postdocs, technicians, and research assistants. The initiative has also received infrastructure funding from the Canada Foundation for Innovation. Yamanaka himself is chair of the initiative’s external advisory board. From MaRS and the Ontario Ministry of Research This is not Yamanaka’s first interaction with Ontario researchers. In 2008, he signed a partnership agreement with Ellis and Bill Stanford—codirectors of the Ontario Human iPS Cell Facility—to share findings, patient samples, and protocols. The Human iPS Cell Facility was begun in 2008 at the Hospital for Sick Children to create and store disease-specific iPS cell lines. Started with seed funding from the Ontario Ministry of Research and Innovation, the facility will receive $1.7 million from the Ontario Initiative in Personalized Stem Cell Medicine to continue its mission. “It was an opportunity to build an infrastructure that would be a benefit to the entire [stem cell] group in Canada,” says Ellis. The facility currently houses iPS cell lines developed directly from patients with a variety of diseases, including cystic fibrosis, musculoskeletal disorders, congenital heart disorders, and more. Though they are increasingly using samples provided by other researchers, Stanford and Ellis have acquired and developed most of the cell lines themselves, including a cell line for Rett syndrome, an autism-spectrum genetic disorder that is a primary focus of Ellis’s research. Because neurons cannot be removed from a patient the same way blood or skin samples can be, Ellis and collaborator Mike Salter, an electrophysiologist at the Hospital for Sick Children, take patient skin samples and use them to create iPS cells, which they can then differentiate into neurons to identify neuronal defects. The researchers are now performing validation studies to verify that the iPS-derived neurons correctly model neurons from the patient brains. “I think the main use of iPS cells is actually going to be to model disease and to screen for drugs,” says Ellis. “An outcome of iPS might not be cell therapy, but personalized medicine.” In addition to the Human iPS Cell Facility, Ontario boasts the Braley Human Stem Cell Library in Hamilton, a platform for high-throughput screening of human stem cells. In addition to the Human iPS Cell Facility, Ontario boasts the Braley Human Stem Cell Library in Hamilton, a platform for high-throughput screening of human stem cells. Led by Bhatia at McMaster, the automated system employs a robotic arm to add compounds from chemical libraries to up to 15,000 wells full of human stem cells. Most of the cell lines used at the facility are iPS lines, and eight of them have been specially constructed with fluorescent tags to report the absence of genes associated with differentiation. That way, researchers can quantitatively measure when a cell exits self-renewal—when it stops fluorescing—and commits to a lineage. “The promise of stem cells is not that they can make copies of themselves, but that they can make something useful—a specific cell type,” says Bhatia. “We can go through lots and lots of compounds this way and find new molecules to improve the differentiation process.” Bhatia is currently using the library to measure the toxicity of potential drugs on healthy stem cells and cancer stem cells. He has been able to differentiate between these two strikingly similar populations thanks to a litmus test his lab developed in early 2009. Stem cell research is a relatively young field, and researchers are often very happy just to see their cells grow, says Bhatia. “Labs should be careful,” he says. “Don’t get too excited about having a really good stem cell, because it may be on the way to becoming a cancer cell.” After years of research, Bhatia and his team proposed a way to measure the balance between self-renewal and a healthy ability to differentiate: a set of eight features to distinguish healthy stem cells from rogue stem cells. They include a quantitative measure of how well a cell line differentiates, the morphology of cell growth in vivo, and the activity of certain transcription factors. Bhatia regularly hears from labs eager to use the test on their own stem cell lines. The Next Generation Ontario’s pool of talent continues to grow. Today’s young PIs are the first generation of researchers actually trained in stem cell techniques, and many of them are setting up shop in Ontario, bolstered by SCN training programs and the collegial atmosphere of the province. A large part of the SCN’s contribution to the community, in addition to annual meetings and funding opportunities, is a commitment to training. Each year the network offers workshops on flow cytometry and hESCs, and it has recently introduced a human iPSC course. SCN also organizes mentorships for new trainees and a course on how to work with industry. The SCN’s training and networking tools were priceless when looking for a job, says Cheryle Séguin, a new PI at the University of Western Ontario. “It’s not just good on paper. It does actually work.” In 2008, Séguin worked with Janet Rossant and Andras Nagy, among others, to differentiate ESCs into endoderm, a developmental germ layer that differentiates into lung, liver, pancreas, and many other cell types in the body. Today, Séguin has her own lab, where she is attempting to differentiate ESCs all the way into pancreatic precursors. “I was really happy that Canada has such a strong stem cell research environment that I could stay and not feel like I was compromising,” she adds. Canadian Lynne-Marie Postovit returned to Ontario in 2007 to join the faculty of the University of Western Ontario after completing a postdoc fellowship at Northwestern University in Chicago. “Ontario is especially supportive of new investigators,” says Postovit, winner of the 2009 Premier Young Researcher Award from CIHR. Since setting up her lab, Postovit, who studies how the microenvironment affects cell behavior and fate, has received funding from the Canadian Foundation for Innovation to purchase state-of-the-art equipment, including big-ticket items that young PIs rarely have in their own labs, like small animal imaging equipment. “There’s money for infrastructure, and a lot of the senior colleagues are willing to support you and not see you as competition,” says Postovit. “There’s a feeling of camaraderie.” Postovit and Séguin, together with two other new stem cell researchers at Western, David Hess and Dean Betts, have submitted a grant to the Ontario Ministry of Research and Innovation seeking funds for a joint project to develop methods to differentiate stem cells into pancreatic islets for future diabetes treatments. “We’re capitalizing on all of us being here now and the collaborative nature of the region,” says Postovit. “This is really the beginning.” Local Government Investment: Ontario Initiative in Personalized Stem Cell Medicine: $11 million Cancer Stem Cell Consortium: $30 million Canada Stem Cell Network: $17 million Global Leadership Round in Genomics and Life Sciences: $100 million Ontario Stem Cell Facilities Braley Human Stem Cell Library at McMaster University, led by Mick Bhatia Ontario Human Induced Pluripotent Stem (iPS) Cell Facility at the MaRS Centre in Toronto, led by James Ellis and Bill Stanford Stem Cell Bioengineering Laboratory at the University of Toronto, led by Peter Zandstra McEwen Centre for Regenerative Medicine at the MaRS Centre, led by Gordon Keller McLaughlin Centre for Molecular Medicine, Regenerative Medicine Program at the MaRS Centre, led by Derek van der Kooy Sprott Centre for Stem Cell Research at the Ottawa Health Research Institute, led by Michael Rudnicki

A Living Legacy

A Living Legacy

At the birthplace of stem cell research, the next generation of scientists continues to advance the field.

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Megan Scudellari

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December 2010

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