UCSF/Nobel Event Explores the Promise of Stem Cells

Enthusiasm, anticipation and a bow to the unknown marked a lively panel discussion with Nobel laureates and UCSF scientists on the leading edge of the stem cell field on Tuesday evening, Sept. 20, at UCSF.

Some 550 members of the public turned out to hear their thoughts. And in the 90-minute presentation - a mix of explanation, debate, reflection -- on the fledgling field, the scientists shared their hopes - and expectations - for exploring the landscape that they say offers the promise of discovery.

Stem cell science is in its infancy, they noted, and the insights that will be made about the human body cannot yet be predicted, but real advances - in the next five to 10 years - are likely, most suggested. "Some reasonable expectations in the near term," said panelist UCSF Chancellor Mike Bishop, MD, "include improvements in the efficiency with which embryonic stem cells can be isolated; the perfection of our ability to grow them strictly with human matter so that they are not contaminated by animal materials; fundamental insights into the chemical signals that tell stem cells to go one way or another, to become a pancreas cell or a blood cell or whatever; and much better definition of adult stem cells." Bishop won the Nobel Prize for co-discovering that cancer is caused by normal genes gone awry, a revelation that has provided underpinnings for advancing the detection and treatment of cancer. Advances are also likely to include finessing the procedure used to create stem cell lines that carry the genetic makeup of patients, several panelists said. They could even include early-stage therapeutic trials - possibly using stem cells in cell-transplant therapy, possibly as vehicles for delivering drugs to damaged tissues. The driving forces of the work, they suggested, will be hope, energy and investigation. At this stage in the development of the field, it's hard to know what the breakthroughs will be, said Bishop. But even if the outcomes are not what are predicted now, he said, "I think there's no question we'll gain profound understanding of the development of the human organism that will have implications beyond anything any one of us could predict." UCSF School of Medicine Dean David Kessler launched the panel discussion with a simple question that led to a far-ranging discussion: just "what is a stem cell?" and what should we expect from these cells for treating disease? "Stem cells have the ability to become any cell type in the body. They also have the ability to self-renew," explained Arnold Kriegstein, MD, PhD, the director of UCSF's Institute for Stem Cell and Tissue Biology. "So, potentially, they offer an inexhaustible source of cells for replacement therapy." But are they really going to be useful in replacing cells damaged by disease, such as heart disease, diabetes and Parkinson's? Kessler probed.

More than 550 people gathered for the Sept. 20 stem cell event, which was simulcast at other UCSF locations. Photos by Christine Jegan.

Nobel laureate Arvid Carlsson, PhD, of the University of Gothenburg, whose research led to the development of L-dopa, the one drug effective against Parkinson's disease, expressed doubt, at least for the brain. "Stem cell research is a very dynamic field and many avenues [should be pursued.] But I doubt very much that within the next 20 years stem cells will offer a successful treatment against any neurodegenerative [brain] diseases," he said. "Arvid, I can only say I hope you're wrong!" laughed UCSF's Stanley Prusiner, MD, director of the UCSF Institute for Neurodegenerative Diseases, whose studies of prion diseases in the brain overturned a tenet of modern biology, determining that a protein can cause disease, for which he won the Nobel prize. "My hope," said Prusiner, "is that we'll see either stem cells as therapeutics, or stem cells as a way to get new drugs, and that this will happen in the next five to 10 years. And that we'll have at least one breakthrough in these degenerative diseases." All agreed that the possibilities -- and the questions to pursue - are extensive: The cells could be used to replace damaged tissues. They could be used as vehicles to deliver drugs into the brain; to test drugs in the culture dish; to create precise models of human disease in mice. Already, stem cells from patients with various diseases are being studied in the culture dish; they are being studied as a cause of some cancers. Stem cells could also cause serious side effects and lead to cancer. 'Expect the unexpected' We should expect the unexpected, said Bishop. Invoking the words of Albert Szent-Gyorgyi, who won the Nobel Prize in 1937 for his research on vitamins, he paraphrased, "When scientists write about their work and their discoveries in retrospect, they describe a perfectly straight line, a relentless progression from one point to another. "The reality," he continued, "looks like the track of a drunken sailor. Many of the steps backwards in the wrong direction by the drunken sailor represent erroneous hypotheses or failed experiments. Many of the steps in the right direction represent the totally unexpected." The cloning of Dolly the sheep was, in a sense, the ultimate stem cell experiment, said Bishop, and was utterly unexpected by the majority of scientists. It had been thought that once a cell had fully matured, it could not be turned back in time. The fact that the DNA of a mature cell could be reprogrammed, he said, was "stunning." An immediate challenge facing the field, the scientists said, is determining how to control stem cell "differentiation." If stem cells could be prompted to specialize, say, as pancreatic islet cells, they could be transplanted into patients, potentially replacing islet cells too damaged to produce insulin. This effort, explained Kriegstein, is taking place in three main types of stem cells -- embryonic stem cells, which form in the four to five days of an embryo's development; stem cells that evolve in particular tissues later in the developing fetus; and adult stem cells that are continually replenished in some adult tissues. "What are the differences?" prodded Kessler. "Mine have more potential," offered Renee Reijo Pera playfully - but truthfully. Reijo Pera, PhD, co-director of the UCSF Human Embryonic Stem Cell Center, is studying how to turn human embryonic stem cells into ooctyes (eggs) and sperm. Her goal? To identify the genetic missteps that sometimes occur. These errors are the No. 1 cause of birth defects and a cause of infertility. Most scientists doubt it will be possible to persuade adult stem cells to specialize into all of the cells of the body the way embryonic stem cells can, said Bishop. But if they're wrong, he noted, it would release the political pressure on the ethical issue of working with human embryos. "I expect this debate will be settled in the next five years," he said. A tool for testing Alzheimer's drugs Even if stem cell differentiation can be controlled in the culture dish, however, the question remains whether the newly specialized cells will prove effective against disease in the human body. Prusiner urged the inquiry, with qualified optimism: "If you look at the field of neurodegenerative diseases, there's been only one really effective drug in the last 40 years, and that's L-dopa, used to treat Parkinson's. And L-dopa only ameliorates the symptoms of the disease - it does not stop its progression. We're looking for new answers, and see stem cells as a way to do this." Cell-replacement therapy, he said, could prove effective in treating neurodegenerative diseases where a single type of brain cell, in a particular region of the brain, is destroyed, as in Parkinson's, ALS (amyotrophic lateral sclerosis) and multiple sclerosis. It is much less likely to prove effective in treating Alzheimer's, Huntington's and prion diseases, where degeneration occurs in many regions of the brain and in many cell types. "We're not going to cure Alzheimer's disease in our lifetime, or the lifetime of our children, with stem cells," he posited, regardless of the therapeutic strategy. Still, he suggested, stem cells could be used to create precise models of these more complex human brain diseases in mice, providing a critical system for studying disease and testing drugs. {pagebreak}

Strategies for treating Parkinson's disease

Carlsson, meanwhile, suggested that Parkinson's studies should focus not on stem cells, but on "prevention - identifying the molecules in our environment that could be important in the etiology of the disease." Kriegstein, however, said that with regard to stem cell research, the question is whether the glass is half full or half empty. There are many avenues to explore, and hints of encouragement even regarding Parkinson's disease, he said. It's possible, he noted, that stem cells could be engineered to express a growth factor known as GDNF, and then infused into the brain to target the dopamine-producing cells that die in the disease. We know now, he said, that some stem cells have an intrinsic ability to migrate to the midbrain, where the disease develops. If these steps took place in mice, he said, clinical trials might occur in as early as three to five years. The upshot, they all agreed, is the need for more research. The potential of stem cells to treat diabetes, for one, is significant, said Jeffrey Bluestone, the director of the UCSF Diabetes Center and one of the world's foremost experts on transplantation immunology and Type 1 Diabetes. Right now, in clinical trials, scientists are transplanting pancreatic islet cells from donated cadavers into diabetic patients, with some success. If scientists could figure out how to prompt stem cells to specialize as pancreatic islets, they could provide an unlimited source of transplantable cells. In which case, said Bluestone, he's confident cell-replacement therapy would ultimately work. Targeting diabetes The prime challenge, he said, would be to make the transplanted cells survive better than they do in the current clinical trials -- to train them to do exactly what they're supposed to do: stay alive and produce insulin. This can only be achieved by retuning the immune system of diabetic patients, to prevent it from destroying the transplanted cells, as it destroyed the original insulin-producing cells in the first place. (Bluestone has developed a monoclonal-antibody-based drug aimed at preventing immune system rejection in several autoimmune diseases. It is being studied in clinical trials.) An additional challenge would be to prevent any undifferentiated stem cells from replicating out of control, the hallmark of cancer. "How are you going to prove to my former agency that the cells are terminally differentiated [i.e., full-fledged pancreatic islet cells]?" prompted Kessler, who was commissioner of the US Food and Drug Administration (FDA) from 1990 to 1997. He'd "fingerprint" the cells, said Bluestone, to make sure than none of them - down to one in 10 million or lower - are anything but fully specialized pancreatic islet cells. "Is this a big issue?" pushed Kessler. "Gigantic." "Are we wasting our money?" asked Kessler. No, said Reijo Pera. "The opportunities to learn are just incredible." Just in the last year, she noted, scientists have begun studying lines of stem cells obtained from embryos created through somatic cell nuclear transfer (SCNT), or "therapeutic cloning." This technique, which involves creating an embryo that has the DNA of a particular individual, allowed scientists in South Korea to create cell lines using the DNA of patients with various diseases, including diabetes. Studies of diseased cell lines could illuminate the genes involved in various diseases and offer targets for therapy and drug testing. "I think we'll answer a lot of questions in the next one to two years regarding SCNT," said Reijo. How quickly the science progresses will depend on how effectively and efficiently SCNT can be carried out. If it's very successful, she said, stem-cell-based therapies derived from SCNT could occur in a few years. On another front, studies are illuminating the role that stem cells may play in causing some cancers, such as leukemias, said Bishop. The hypothesis, he said, has "radically transformed" the way we look at the disease. The failure of surgery, radiation and chemotherapy to eradicate some cancers may occur, he said, because the arsenal does not target the initial source of the disease. "If we could identify a tumor stem cell [in a given tissue], we could target this," he said. Ethical guidelines for the science With the stakes so high for patients, and the scientific questions still so fundamental, what is the appropriate balance for ensuring that ethical guidelines are in place as the field moves toward clinical trials? asked Kessler. The field must carefully assess the ethical implications of the studies underway now, as well as those of the clinical trials envisioned for the future, said Elena Gates, MD, a leader in addressing the ethical issues of reproduction and embryonic stem cell research and interim chair of the UCSF Department of Obstetrics, Gynecology and Reproductive Sciences. The May 2005 recommended ethical guidelines issued by the National Academy of Sciences were an important starting point. But because the National Institutes of Health (NIH), the primary federal biomedical research funding agency, does not support a broad degree of human embryonic stem cell research, many of the ethical issues that normally would have been addressed by the NIH must be addressed, instead, by the states, academic universities and biotechnology companies carrying out the research. UCSF's Campus Advisory Committee on Human Gamete, Embryo, and Stem Cell Research has been examining the issues since it began its pioneering human embryonic stem cell studies in the late 1990s, said Gates. Earlier this month, members of this UCSF committee published recommended guidelines relating to future clinical trials in the journal Stem Cells. The goal of the guidelines is to promote both the confidentiality of people who donate the embryos, oocytes (eggs) and sperm that contribute to the development of embryonic stem cells, and the safety and well-being of the patients who would participate in clinical trials. A mistake, she said, would be to move too fast, as occurred in early trials of gene therapy. "Gene therapy promised too much too soon," said Bishop. "We leapt ahead in our vision without all the tools." But, he said, he still expects dramatic results with gene therapy in the future, and points to the success in treating the "bubble" children, those with SCIDs (severe combined immunodeficiency syndrome). "There have been complications in these children, but they have been addressed. Fundamentally, the treatment of SCIDs is an example of gene therapy curing a horrible disease." Stem cell research, he said, is a field that offers too much promise not to explore. In recognition of the co-sponsors of the panel event, the consulates of Sweden and Norway on the occasion of the 100th anniversary of the establishment of the Nobel Prizes, Bishop concluded with the following reflection by Alfred Nobel on why he had established the Nobel Prizes. "He explained," said Bishop, "[that he] wanted to help dreamers, because dreamers have a great problem getting on in life. What we're talking about here is a dream. And nothing ventured, nothing gained. "We really must pursue [the field] to a rigorous conclusion." The stem cell event will be broadcast on KQED radio (88.5 FM) on Thursday, Sept. 29, at 8 p.m. and again on Friday, Sept. 30, at 2 a.m.) For more information on stem cells and UCSF's stem cell program, go here. The stem cell event was arranged in conjunction with "The Nobel Prize: 100 Years of Creativity," a traveling exhibit at the Exploratorium. The exhibit runs until Oct. 2, 2005. Source: Jennifer O'Brien

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