From left, UCSF scientists Arturo Alvarez-Buylla; Harold Bernstein; and Arnold Kriegstein, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF; Dave Iverson, KQED radio host and co-producer and co-director of the PBS Frontline film My Father, My Brother, and Me; and UCSF scientist Thea Tlsty.
By Suzanne Leigh
Stem cell researchers at UCSF are at the forefront of their field, despite the political challenges and federal funding shortfalls faced during the last decade, said Arnold Kriegstein, MD, PhD, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF in a panel presentation on May 7.
Thanks to funding from philanthropists, foundations and the California Institute for Regenerative Medicine (CIRM), a state agency established through the passage of Proposition 71 in 2004, UCSF has been able to expand its program from a small, pioneering center of stem cell research into one of the largest, most prodigious in the world, said Kriegstein. Top young scientists have been recruited, laboratory space has been renovated, research grants have been awarded – and major scientific strides have been made.
Funding from donors and CIRM will enable UCSF to open a stem cell research building on its Parnassus campus in 2010. The $123 million building, housing 25 scientists, will be the campus’s first research center to open since the construction of the Health Sciences towers in the mid-1960s.
That said, the ongoing “enormous competition for research dollars” from the National Institutes of Health means that other sources of funding particularly for some of the more novel, and thus risky, investigations remain, said Kriegstein, noting that there has been no increase in the National Institutes of Health budget for five years.
Still, the revocation of former President George W. Bush’s stem cell policy gives scientists a new edge: With the exception of creating new human embryonic stem cell lines with federal funds, scientists no longer will be required to partition their federal and nonfederal research into different operations, which limited collaboration and necessitated duplicate labs and equipment, said Kriegstein.
Joining Kriegstein on the panel, presented by the UCSF Foundation in San Francisco’s Westin St. Francis Hotel, were fellow members of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research: Harold Bernstein, MD, PhD, professor of pediatrics (cardiology); Jeffrey Bluestone, PhD, director of the UCSF Diabetes Center and the Immune Tolerance Network; Arturo Alvarez-Buylla, PhD, professor of neurological surgery and a principal investigator at the Brain Tumor Research Center at UCSF; and Thea Tlsty, PhD, professor of pathology and a program leader at the Helen Diller Family Comprehensive Cancer Center.
The discussion was moderated by Dave Iverson, KQED radio host and co-producer and co-director of the PBS Frontline film
My Father, My Brother, and Me, a personal journey about his family’s experience with Parkinson’s disease.
Three Types of Stem Cells
The discussion covered three types of stem cells. Embryonic stem cells are found in fertilized eggs and are pluripotent, meaning they can differentiate into any cell type (muscle cell, red blood cell, brain cell, etc.). Adult stem cells are present before birth, but form later on in development and are considered multipotent. These cells are already partially differentiated and their fates are relatively limited.
The third type of stem cells was discovered in humans two years ago by Japanese researcher Shinya Yamanaka, MD, PhD, of UCSF’s Gladstone Institute of Cardiovascular Disease and Kyoto University. Remarkably, Yamanaka uncovered a vast stem cell gold mine when he reprogrammed mature skin cells to make induced pluripotent stem (iPS) cells. These cells appear to match embryonic stem cells’ ability to differentiate into any cell type. Using iPS cells for potential treatments sidesteps ethical concerns associated with embryonic stem cells, and their use may circumvent the problem of rejection, which can occur with donor organs.
“This is a very young area of research,” Kriegstein told the audience. “We know that embryonic stem cells are the gold standard in terms of differentiation. These iPS cells are very similar, but we don’t know exactly how they compare.”
Eventually, iPS cells may be used in regenerative medicine to make new tissue for transplant patients, as well as to help scientists understand the mechanisms of disease in order to develop more effective treatments.
Promising Treatments
One of the most promising arenas for the use of stem cells is in the treatment of heart failure, the result of a loss of heart muscle cells. This can be prompted by heart attack or hypertension, and leads to the compromised ability of the heart to pump oxygenated blood to the body’s tissues.
Jeffrey Bluestone, director of the UCSF Diabetes Center and the Immune Tolerance Network, says the use of stem cells to treat type 1 diabetes is likely on the near horizon.
Heart failure affects 5 million people in the United States, costs the health care system more than $30 billion per year and has serious quality of life issues for patients, said Bernstein. “The only definitive therapy is heart transplantation, but there are not enough organs and not everyone is a transplant candidate.”
Cell transplantation is expected to be a less invasive procedure than heart transplantation, he said. Animal studies with stem cells have resulted in tumors or failure to integrate into the tissue and to conduct electrical signals that enable the heart to pump blood effectively. But Bernstein is confident that his colleagues have the tools to help them identify the cells with the properties they need to develop successful cell transplantation. Human clinical trials could start within five years, he predicted.
Using stem cells in the treatment of type 1 diabetes may become standard treatment even sooner, according to Bluestone, who estimated human trials could start within two to three years.
Unlike the more common type 2 variant, type 1 diabetes is an autoimmune disorder, typically striking children or young adults. It results in the destruction of beta cells, which produce the insulin needed to control blood sugar. Patients are required to monitor their blood sugar and take insulin for life, since the condition can lead to kidney failure, neuropathy, and foot or lower leg amputation if it is inadequately controlled.
Transplantation from cadaveric donors of islets, the clusters of cells in the pancreas that contain beta cells, has freed approximately 300 patients from requiring insulin and glucose monitoring. But the procedure is not a magic bullet, said Bluestone.
“Even if we could use every cadaver available, we would still be treating about 0.2 percent of patients with type 1 diabetes – and rejection is a common problem,” he said, acknowledging the complications of lifelong immunosuppressant treatments.
But using embryonic stem cells and coaxing them into pancreatic beta cells have been very successful in mice. A partnership with the stem cell engineering company Novocell could pave the way to a viable human treatment, Bluestone said.
He compared the odyssey that has taken researchers from embryonic stem cells to pancreatic beta cells to a cross-country journey from San Francisco to New York. “We’re not in New York yet, but we’re getting close,” Bluestone said. “We’re in Newark.”
Epilepsy and Parkinson’s disease are two disorders characterized by overactivity in areas of the brain, resulting in seizures or tremors. Unlike with other approaches that have focused on replacing the dopamine-producing cells that die in Parkinson’s, Alvarez-Buylla is transplanting neural stem cells that migrate and integrate into existing neuronal circuits. In animal models of Parkinson’s, the transplanted cells resulted in improved motor tasks, he said.
Similarly in epilepsy, studies on animals are showing that grafted neural stem cells mesh with the brain’s neural circuitry and reduce seizure frequency. Human trials for both conditions are expected to start in about five years, said Alvarez-Buylla.
Just as stem cells have the potential to heal, it is now widely believed that certain stem cells can be the driving force of brain tumors and some cancers. Alvarez-Buylla is also looking at how neural stem cells express the receptor for the growth factor PDGF, which regulates cell growth and division. Overstimulation through this receptor can result in tumor-like masses, according to research in Alvarez-Buylla’s lab.
“Stem cells can help us understand the mechanism of disease and ultimately lead to more targeted treatments for brain tumors and other cancers,” he said.
The presence of cancer stem cells explains why radiation and chemotherapy can have limited effectiveness, said Tlsty. Like all stem cells, cancer stem cells are essentially immortal – they divide and self-renew throughout life.
A tumor may contain a tiny minority of cancer stem cells, but these are the ones that appear to be most resistant to chemotherapy or radiation treatments.
“A cancerous tumor is like a weed,” said Tlsty. “Current treatments don’t reach the roots of the weed. So cancer regresses for a period of time, but may eventually grow back.”
The answer may ultimately lie in “selectively repackaging the DNA” of cancer stem cells to make them normal, she said.
Photos by Noah Berger
