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UNLOCKING
PROMISE OF STEM CELLS
But what if those cells - or other types of stem cells - could be harnessed to save millions more lives? What if they could replace heart muscle cells killed by heart attacks? Or restore insulin-producing beta cells in diabetics? What if they could build nerve bridges across severed spinal cords? Regenerate dopamine-producing brain cells for people with Parkinson's disease? Rev up the immune systems of people infected with HIV? Or grow new skin for burn patients? Those are among the dreams of scientists involved with stem cell research. "The way things are going, I won't call it science fiction, but a real possibility," said Iqbal Ahmad, a molecular and cellular biologist who directs the Medical Center's Neural Stem Cell Research Program in Omaha. Turning that possibility into reality faces many hurdles, not the least of which is a political, ethical and legal debate over acceptable sources of stem cells. At their most basic, stem cells are cells that can divide indefinitely and produce more specialized cells. The very first cell of a human's life -- the fertilized egg -- is a stem cell. It is called totipotent because it can do it all. From it grows the embryo and the placenta, the amniotic sac and the developing fetus. Descendants of that cell comprise the more than 200 types of specialized cells that make the human body function. All of the 100 or so cells that form week-old embryos are stem cells, too. They already have lost some potential - they cannot form a placenta or amniotic sac. But they are pluripotent and can become any other part of the developing human. That broad potential makes embryonic stem cells the focus of considerable excitement among both scientists and patient groups. Two teams of researchers - one in Wisconsin and one in Maryland - have already figured how to keep embryonic stem cells alive in the laboratory. And a world of promise opens up if scientists can figure out how to steer them down desired paths. The cells could unlock the mysteries of human development and show what goes wrong in some babies. They could be used to test drugs and chemicals, showing how they affect human cells without putting human beings at risk.
And they could provide the cells, and maybe even organs, needed to return diseased or damaged bodies to health. "Almost any disease or injury that you can imagine. anything from spina bifida to spinal cord injury could be treated," said Daniel Perry, chairman of the national Patients Coalition for Urgent Research. But using human embryonic stem cells means destroying an embryo, which many call an unethical and immoral act that should put the research off limits despite its promise. "There's the basic principle that we apply and that ethics applies and that is: Do no harm. Research should be at the service of life and not the other way around," said Greg Schleppenbach, director of the Catholic Bishops' Pastoral Plan for Pro Life Activities. By the time humans are born, and after they grow up, they still have stem cells - adult, multipotent stem cells with more limited potential. Each type of adult stem cell produces only a few types of body tissue - only blood cells or only skin cells or only intestinal cells. And some types of body tissue don't appear to have stem cells. These cells are valuable. Just ask Dyer and others who have been treated with blood stem cells. But they can't do as much as their embryonic counterparts. At least that's been the established belief. Yet every month brings new reports about stem cell discoveries, based on both embryonic and adult, animal and human cells. And with every report, it seems a little more of the previously accepted biological knowledge disappears. "You have to be very careful with dogma in this field," said J. Graham Sharp, a Medical Center cell biologist who heads a cluster of adult stem cell research projects. "So much of it has been overturned." Take Ahmad's work, for example. Until four years ago, he taught students the brain could not renew itself, that humans are born with a set of brain cells that would have to carry them through their whole lives. "That dogma was so deeply entrenched that even in the face of overwhelming evidence, it persisted," he said. The evidence came from both animal and human sources. Some 30 years ago, researchers found a dividing population of cells in the learning center of rat brains. Dividing cells are a hallmark of stem cells.
Researchers also knew that olfactory neurons, or nerve cells, in the nose regenerate. They have to, or humans and other animals soon would lose the ability to smell. Olfactory neurons are part of the brain, Ahmad said, but they were dismissed as a special case. More research showed that the brains of songbirds - even adult birds - undergo tremendous change from season to season. Then scientists found that the new olfactory neurons develop deep inside the brain and migrate to the nose. They come from stem cells along the ventricle, or cavity, in the center of the brain. Finally, a series of experiments with animals showed the brain indeed has stem cells, that those cells will grow in the laboratory and can be induced to form a variety of brain cells - including neurons and supporting cells - and that the laboratory-produced cells can repair brain damage in mice. "There was emerging evidence that neurons could be replaced," Ahmad said. "There are new neurons, whether it is in response to injury or it is in response to new requirements." His own research started with a related question. He knew the retina is an extension of the brain. So if stem cells could replace the missing brain cells in mice with a version of Lou Gehrig's disease, could they replace the damaged cells of rats with retinitis pigmentosa? Using rat embryonic stem cells, he found the answer was yes. But would it work in humans? To know that answer, he had to find a source of human stem cells. And federal funding was banned for work with human embryonic stem cells at that time. Ahmad started his search with what he knew of frogs and bony fish eyes. He discovered stem cells at the same place in human eyes as in the eyes of those creatures, lying dormant in the ciliary body. That body surrounds the lens of the eye and maintains proper pressure in the eyeball. Stem cells from the ciliary body, he found, tend toward creating retina cells. Yet when transplanted into other parts of the brain they can become any of the three main types of brain cells. "We found they are very plastic," he said. "Not only does it divide but it is plastic enough to give rise to neurons and glia and astrocytes. In a heterotopic site, it acquires the property of that site." Ahmad's research opens up the possibility of finding a ready source of stem cells for transplanting into people with brain diseases. Donor eyes already are commonly taken from cadavers. Maybe, some day, stem cells could be cultured from those eyes and transplanted into people suffering with Parkinson's disease or Alzheimer's disease, stroke or head injury, to replace their damaged brain cells. Or maybe small pieces of the ciliary body could be surgically removed from people with brain diseases, the stem cells cultured and given back to heal them. "The way things are moving, I don't think it is far off that stem cells taken from adult human beings could be transplanted," Ahmad said. So why the need for a debate about the sources of stem cells? Why not just use adult stem cells, which almost everyone agrees is moral and ethical? Pro-life groups often make that argument, along with calling for a ban on human embryonic stem cell research and use. A position statement from Do No Harm: The Coalition of Americans for Research Ethics, founded by a number of scientists, said: "Destruction of human embryonic life is unnecessary for medical progress, as alternative methods of obtaining human stem cells and of repairing and regenerating human tissue exist and continue to be developed." But many scientists - even those whose work focuses on adult stem cells - are unwilling to close off the avenue of embryonic stem cell research. "The data is not there," argued the Medical Center's Sharp. "We have absolutely no idea what the true potential of adult stem cells are versus embryonic stem cells and fetal stem cells without doing comparison. "I think it would be very dangerous to make that assumption that adult stem cells can do everything." Medical Center Chancellor Harold Maurer said the questions researchers want to find answers for also affect which type of stem cell should be used. "We hope that adult stem cells can be made into 100 percent (as useful as embryonic stem cells)," he said, "but that's not where the science is, at this point, so we're looking at other alternatives." So far, the Medical Center has not started any research using human embryonic stem cells, Maurer said. But Sharp is heading up a cluster of projects aimed at finding out more about what adult stem cells can do. In one project, Ahmad is trying to figure out whether adult blood stem cells can produce brain cells. So far, the answer appears to be yes. The next step is to see whether stem cells from umbilical cord blood can do the same. "It could work out that all stem cells in adults are the same," noted Dr. Anne Kessinger, an oncologist and associate director for clinical research at the Medical Center's Eppley Cancer Center. A pioneer in the treatment given Dyer, Kessinger is studying why some people crank out blood stem cells in response to growth factors and others don't. Other Medical Center researchers are looking at ways to pick out adult stem cells from ordinary cells, whether adult stem cells can grow new blood vessels and new heart muscle in damaged hearts, whether liver stem cells can carry new genes into a diseased organ and whether stem cells can be found in human lungs. Those experiments and others going on in laboratories around the world may yield more miraculous treatments based on adult stem cells. But adult stem cells haven't been found for every type of tissue and no one knows how well they will work at various tasks, Sharp said. Can adult stem cells from the eye produce neurons that will make the right kinds of connections with other brain cells, for example? How long can the new neurons live? Can adult stem cells produce enough neurons to make a difference? Will they cause unforeseen side effects? Many of the same questions remain to be answered for embryonic stem cells as well. Ahmad has been able to use animal embryonic stem cells to find his answers. But that wouldn't work for all research questions, he said. "We have been lucky that so far it has worked fine." Supporters of embryonic stem cell research argue that only research on both types of stem cells can show whether one yields better answers than the other. "Patient organizations have said we should push ahead on adult stem cells and we should push ahead on embryonic stem cells and fetal germ stem cells," said Perry of the national Patients Coalition for Urgent Research. "Because patient needs are so critical that we cannot afford to only do research on adult stem cells and then find out it won't work." Reach Martha Stoddard at 473-7245 or mstoddard@journalstar.com.
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