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Stem-Cell Promise Awaits Results Progress in labs both greater and less than it seems Ethical debate and political realities cloud research GINA KOLATA - NEW YORK TIMES Sep. 5, 2004. 01:00 AM BOSTON—At three laboratories here, the world of stem-cell research can be captured in all its complexity, promise and diversity. One of the labs focuses on cells taken from human embryos, another on cells from mice and fish, and the third from stem cells that have mysteriously survived in the adult body long after their original mission is over. But while the work here and elsewhere has touched off an ethical debate reaching into the U.S. presidential campaign, a tour through these labs shows that the progress of research is both greater and less than it seems from a distance. One idea, the focus of about half of U.S. stem-cell research, involves studying cells that are naturally present in adults. Researchers have found such cells in a variety of tissues and organs and say they seem to be a part of the body's normal repair mechanism. There are no ethical issues in studying these cells, but the problem is in putting them to work to treat diseases. So far, no one has succeeded. The other line of research, with stem cells from embryos, has a different obstacle. In theory, the cells could be coaxed into developing into any of the body's specialized cells, but so far scientists are still working on ways to direct their growth and they have not effectively cured diseases, even in animals. The most progress with embryonic stem cells is in mice, with one group of researchers directing the cells to grow into a variety of blood cells, but not yet the ones they want. Another group directed mouse stem cells to grow into nerve cells and tried to use them to treat Parkinson's disease in mice. The nerve cells produced the missing chemical, dopamine, but not enough of it to cure the disease. At the Tufts New England Medical Center here, Dr. Diana Bianchi's foray into the world of stem-cell research involved a decade of discoveries so unexpected that colleagues at first looked askance. Bianchi stumbled into the field when she was trying to find a new method of prenatal diagnosis. She knew that a few fetal cells enter a woman's blood during pregnancy and hoped to extract those cells for prenatal diagnosis. That proved too difficult because there are so few fetal cells in maternal blood. But then she discovered that the fetal cells do not disappear when a pregnancy ends. Instead, they remain in a woman's body for decades, perhaps indefinitely. And if a woman's tissues or organs are injured, fetal cells from her baby migrate there, divide and turn into the needed cell type — be it thyroid or liver, intestine or gallbladder, cervix or spleen. One woman Bianchi studied had hepatitis C, a viral infection. When her liver repaired itself, it used cells that were not her own. "Her entire liver was repopulated with male cells," Bianchi says. In theory, fetal cells lurking in a woman's body are the equivalent of a new source of stem cells and could be stimulated to treat diseases. But, Bianchi says, she does not yet know for sure that the cells are stem cells — she must isolate them and prove they can turn into any of the body's specialized cells — or where the cells reside, or how, short of injury, to spur them to action. At nearby Children's Hospital, Dr. Leonard Zon, chief of stem-cell research, and his colleague, Dr. George Daley, are working with stem cells from embryos, using mice and zebra fish in hopes of learning to transform the stem cells into immature blood cells that will divide and replenish themselves. If they can apply their work to human embryonic stem cells, they want to use the cells instead of bone marrow transplants to treat patients with genetic disorders like sickle cell anemia, and inborn disorders of the immune system. So far, in research that stem-cell investigators say is among the most promising in the field, Zon and Daley have turned mouse embryonic stem cells into mouse blood cells. Those blood cells, however, are more mature than the ones they need, a particular type of early blood cells that can repopulate a patient's bone marrow and survive indefinitely. Ones that are more mature live out their lifespans and die within weeks. They are also working with human embryonic stem cells, venturing into the most controversial area of stem-cell work. Human embryonic stem cells are derived from human embryos, about a week old, and the only way to get the stem cells is to destroy the embryos. Some human stem cells came from embryos that were donated by couples at fertility labs that had embryos left over after they decided their families were complete. Others came from embryos that were created to obtain stem cells; researchers paid women to donate eggs, fertilized them and let them grow to the stage where stem cells could be extracted. The government has agreed to pay for research with human stem cells, but only for work with 22 lines of cells; each line is the progeny of a single embryo. The restriction dates from Aug. 9, 2001, when President George W. Bush issued a directive saying the government would fund research only with cell lines created before that date. Dr. James Battey, director of the National Institute on Deafness and Other Communication Disorders and chairman of the National Institute of Health's stem- cell task force, says scientists are free to study other stem-cell lines if they use private money. He says he understands the researchers' complaints that it would be better if the government paid for work on more lines, but the government's "argument isn't solely about science ... This is a White House policy. It is not based solely on the needs of the scientific community." Over at Harvard University, a stem-cell project is becoming a world supplier of 17 lines of human embryonic stem cells, created without cloning, and made from 286 frozen embryos created by in vitro fertilization. But the four scientists involved in the privately funded research want to plunge into one of the most controversial areas of stem-cell research — creating human embryos by cloning and obtaining stem cells from those embryos. An embryo created by cloning would be an exact genetic match of the person whose cells were used to make it. Its stem cells and any mature cells derived from those stem cells would exactly match the cells in the person's body, making them perfect replacement cells. Meanwhile, the national debate over human embryonic stem cells continues. While many Americans say in polls that they favour using these cells, many others say creating and destroying a human embryo to obtain the stem cells is ethically unacceptable. And they insist that doing research on human embryonic stem-cell lines that are already in existence does not right the wrong. The challenge in the midst of a fierce political debate, many scientists say, is to be realistic about how hard it is to develop treatments. Battey lists some of the challenges ahead: getting the cells to develop into exactly the adult cells that are needed, demonstrating that the adult cells can survive, preventing rejection and controlling cell growth. Such issues, he says, "need to be addressed in animal models before any thoughtful person would go into humans." 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