Despite roadblocks, California's stem cell initiative shows promise
From the April ACP Observer, copyright © 2007 by the American College of Physicians.
By Yasmine Iqbal
Robert H. Blelloch, MD, PhD, an investigator at the University of California, San Francisco School of Medicine, has been receiving support from the National Institutes of Health for his research into the developmental potential of stem cells. But when he wanted to expand into experimenting with human embryonic stem cells, that funding source could not be used.
Fortunately, California's Proposition 71 allowed him to get around the federal government's August 2001 ban on funding for experimentation on all but a handful of human embryonic stem cell lines. In February, Dr. Blelloch was among the first group of researchers to receive grants through the California Stem Cell Research and Cures Initiative, or Proposition 71. The 2004 initiative promised to distribute $3 billion in research funding over 10 years.
"If this grant hadn't come through, I wouldn't have been able to proceed with this project," said Dr. Blelloch, whose research holds promise for the development of new cancer treatments. The NIH spent about $38 million on human embryonic stem cell research last year but the Bush administration has banned such funding for work with embryonic stem cells derived after August 2001.
California's initial $3 billion, which was supposed to have come from bonds that were to be sold over a 10-year period, had been tied up in lawsuits that challenge the measure's constitutionality. Nevertheless, on Feb. 16, 2007, the California Institute for Regenerative Medicine (CIRM), the state agency created to make the grants and oversee the funds, approved its first round of 72 research grants totaling approximately $45 million over two years to academic and research centers across the state. Then, just 10 days after CIRM's disbursement, a state appeals court ruled Feb. 25 that the program could proceed because it did not violate any of the issues alleged in the lawsuits.
The fact that the checks will soon be in the mail is the result of extraordinary maneuverings on the part of private philanthropists and the state government, who did not wait for the state appeals court's decision or any possible appeals to the state Supreme Court that may occur.
In July 2006, Gov. Arnold Schwarzenegger approved a $150 million loan from the state's General Fund (once Proposition 71 bonds can be sold, the money will be used to pay back this loan, with interest). Private philanthropists chipped in with $45 million by purchasing bond anticipation notes, which will also be paid back when the bonds are sold. As a result, CIRM collected nearly $200 million.
The resulting Scientific Excellence through Exploration and Development (SEED) Grants were awarded to both new and seasoned investigators, like Dr. Blelloch, who had new ideas in the field of human embryonic stem cell research. The 29-member Independent Citizen's Oversight Committee (ICOC), CIRM's governing board, had originally planned to approve only 30 grants totaling $24 million but elected to increase the amount because they received so many high-quality proposals.
CIRM will release another round of funding in March 2007, when it is slated to approve 25 grants totaling $80 million for established stem cell scientists. Claire Pomeroy, MD, MBA, Vice Chancellor for Human Health Services at the UC Davis Health System and a member of the ICOC, said that all grants will be awarded based on the quality of the research proposal and not clustered in any one field.
"When we were creating our strategic plan, we determined that it would be wrong to try to predict in what field the research would make the most difference," she said. "What we need to do is pursue multiple fields of investigation and let the science decide what will ultimately pay off."
"It's a mistake to bet on any one area; we should be betting on high-quality work," agreed Lawrence S.B. Goldstein, PhD, Director of the UC San Diego Stem Cell Program. "I think they've (CIRM) done a good job of choosing projects with ideas and methods that are capable of answering a question clearly, in which we'll learn something no matter what the outcome."
Training the next generation
Although the Feb. 16 grants were the first ones earmarked for actual research, this was the second time that CIRM's coffers had opened. In April 2006, the agency granted $12.1 million to 16 nonprofit institutions, including the California Institute of Technology, the Scripps Research Institute and UC Davis, to establish training programs to educate the next generation of stem cell researchers.
The California Institute for Regenerative Medicine awarded its first round of 72 research grants in February to establish training programs to educate the next generation of stem cell researchers, such as UC Davis MD-PhD student Joyce Ma, shown pipetting cell culture media from a centrifuge tube.
UC Davis MD-PhD student Joyce Ma was one of the young scientists chosen for such a training program last year. Ms. Ma had already been a part of the first research team to identify specific stem cell markers in glioblastomas, the most common and deadliest type of adult brain tumors. "Our lab was the first to identify exactly where these stem cells are located in the human brain," she said.
The research created quite a stir when the group presented their findings at the American Academy of Neurology and the American Association of Neurological Surgeons last year. However, funding was always a worry. "Even though we were working with adult stem cells (and not subject to federal restrictions), there were no funds that were earmarked for this research, and we had to keep asking for money." Ms. Ma estimated that she spent up to 20% of her time applying for grants.
CIRM funds will now help pay for two years of graduate research. "I finally get to spend all the time I want in the lab," said Ms. Ma. She has shifted her focus to the study of the role that stem cells play in multiple sclerosis. Her research strategy involves creating a genetically modified mouse in which the resident stem cells of the brain that respond to injury are labeled with fluorescent proteins and then examining the effects when MS-like lesions are induced.
Stem cells as 'model organisms'
Ms. Ma's research is an example of the general shift in thinking that is occurring among stem cell researchers. Instead of using the stem cells themselves as therapy to help recreate tissues and organs, more researchers are using them to unlock the mechanism of disease processes.
For example, at California Pacific Medical Center Research Institute in San Francisco, researcher Dieter C. Gruenert, PhD, is in the process of generating embryonic stem cell lines that carry the genetic mutation that causes cystic fibrosis and sickle cell disease. "When we have the cells that have the mutations, we can study their characteristics and determine when in their development it would be appropriate to do a therapeutic intervention," he said.
The standard way of studying disease is to use a mouse or other animal model. "However, stem cells give us the unique opportunity to study human diseases in human cells," said Arnold R. Kriegstein, MD, PhD, director of developmental and stem cell biology at the UCSF School of Medicine. "It also gives us a new target for testing and developing drug therapies."
|
"There's always been the hope that we can use stem cells to create tissues and organs, but researchers are now understanding that this is a long-term objective." —Irving L. Weissman, MD, PhD |
"There's always been the hope that we can use stem cells to create tissues and organs, but researchers are now understanding that this is a long-term objective," said Irving L. Weissman, MD, PhD, director of the Institute of Stem Cell Biology and Regenerative Medicine at Stanford University. "Right now, the most important outcome from this research is to get an authentic model for the study of human disease."
Stem cell research has already given scientists a new model for understanding how cancer cells operate. "We now know that a cancer tumor contains a heterogeneous population of cells," explained Dr. Blelloch. "Some of them are cancer stem cells, and only they have the capability to self-renew and create new tumors, causing the cancer to spread. The other cells can divide, but only in a limited fashion, and they eventually run into a dead end. The challenge is to identify the cancer stem cells and figure out how to destroy them.
"This is a new way of thinking about cancer," continued Dr. Blelloch. "In the past, there's been a lot of emphasis on the genetic mutations that cause cancer, but studying the mutations in the context of how the cancer develops has been underappreciated. Stem cells give us a model for understanding what the genetic mutations are causing the cancer cells to do."
Stem cells as therapy
Physicians have been using some adult stem cells, such as hematopoietic stem cells that form blood cells, in bone marrow transplants for many years. Scientists are hoping that they will find other ways of using the stem cells themselves as cures for disease, but they warn that it will be years before stem cell-derived therapies for common maladies such as diabetes and heart disease are common.
"With the exception of adult bone marrow cells, it's very early to be talking about long-term stem cell therapies," said Dr. Goldstein. "We're in the nascent stages, even though the research looks very promising."
For now, one of the most notable experimental stem cell therapy trials is the effort to cure Batten disease, an incurable disorder caused when genetically defective brain cells fail to make a key enzyme that helps dispose of cellular waste. The waste accumulates in the cells, causing seizures, paralysis and death by the teens.
In November 2006, a seven-year-old boy was the first to receive an injection of nerve stem cells derived from fetal tissue. The hope was that the stem cells would spread throughout the brain and produce the missing enzyme. So far, the results look promising. The boy has left the hospital and has regained some of his ability to speak.
But researchers warn that this is a special case. "In this kind of therapy, we don't want the stem cells to differentiate any further. We basically just want them to produce an enzyme that rescues nerve cells that would otherwise die," said Dr. Kriegstein. "That's different from inducing cells to help regenerate tissue."
Also, there's no guarantee that the Batten trial will be a success, and previous fetal cell transplants, including those involving Parkinson's disease patients, have failed to show dramatic long-term improvements.
Getting cells to differentiate and integrate with existing tissue remains one of the holy grails of stem cell research. "Instead of regenerating an entire organ, we might be able to someday develop cells that act as a 'patch' to replace the dead cells and make the organ whole again," said Dr. Gruenert. This would have applications in repairing diseased blood vessel, heart muscle or spinal cord tissue. Replacing cells that produce a key substance, such as insulin or dopamine, is also a key goal.
"Eventually, we might be able to program an individual's own stem cells to repair damage caused by disease," said Dr. Gruenert. "Combined with genetic therapies, this research gives us a whole new perspective on medicine and what we're capable of doing."
An ongoing ethical debate
As passionate as the investigators are about their work, they still urge caution and restraint. "There's a misperception that stem cells are somehow magical," said Dr. Kriegstein.
Dr. Goldstein agreed. "Everyone wants a miracle overnight, but developing this research is a long, painstaking business, and we need to be very cautious." He pointed out, for example, the need to develop basic safety measures.
|
"We know how to get stem cells into the body, but we need to have methods to keep those cells contained and get them out if necessary." —Lawrence S.B. Goldstein, PhD |
"We know how to get stem cells into the body, but we need to have methods to keep those cells contained and get them out if necessary," he said. "I don't think we've thought hard enough about that."
And basic ethical issues may never be fully resolved. "A significant number of people believe that an embryo is a human being, so the question of whether some types of stem cell research destroys human life will continue to be asked," said Faith T. Fitzgerald, MACP, professor and assistant dean of humanities and bioethics at the UC Davis School of Medicine.
She also noted that the processes by which stem cells are harvested, preserved and guided into new creation is all scientific technique that could be patented, and the scientific community must work out systems by which this knowledge can be disseminated fairly.
"It's reassuring that there's so much argument and debate going on about these issues," she said. "The danger lies in total agreement. The advance of science needs vigorous advocacy, but so too does it benefit from the critical analysis of the methods and ethical probity of that science and its implications for humanity."
Hope tempered with caution
The 29 members of the Independent Citizen's Oversight Committee that governs CIRM are especially aware of the need to keep the public engaged while managing expectations. "We're honored that the voters have entrusted us with this huge infusion of funds, but we must give realistic hopes to patients and do the research responsibly and ethically," said Dr. Pomeroy.
But clinical applications are never far from their minds. Each ICOC meeting begins with a patient spotlight, in which a person with a devastating illness or injury talks about the hope that stem cell research brings to him or her. Past speakers have included a young man with ALS and a woman who became a quadriplegic at age six after a gymnastics accident.
"Some of these patients tell us that they hope to walk again," said Dr. Pomeroy. "Others say that even though they know the research we're doing probably won't benefit them, they hold out the hope that others in their condition will be helped."
"The courage of these patients is so amazing, and they help us realize the impact that this research will have," she said. "They remind us why we're doing this work."
Contact ACP Internist
Send comments to ACP Internist staff at acpinternist@acponline.org.