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May 30, 2000 Neural Cells, Grown in Labs, Raise Hopes for Brain Disease Cures Sylvia Elam saw the benefits of her operation as soon as she was wheeled into the recovery room and ate lunch. For the first time in years, she could taste the food. After a stroke in 1993, Mrs. Elam, of Scottsdale, Ariz., lost most of the movement and sensation on her right side. But last year she became one of the first people in the world to have cells manufactured in a laboratory implanted into her brain. The implant enabled Mrs. Elam, now 66, to talk again without stammering, to throw a ball with her right arm, to walk somewhat without a cane and even to drive a car. "It was absolutely beyond our wildest dreams," said Mrs. Elam's husband, Ira. Not all cases have had such positive results, but hope is growing that neural cells implanted into the brain can replace damaged cells and restore functions lost to stroke, spinal cord injury or neurological diseases like Parkinson's and Alzheimer's, most of which have no effective treatments. "It's almost like reseeding your lawn," said Dr. Evan Y. Snyder, a neurologist at Children's Hospital in Boston and at Harvard Medical School, who has successfully used the technique to treat rats with a disease similar to multiple sclerosis. In Mrs. Elam's case, a few months after the operation she suffered setbacks as a result of a second, apparently unrelated, stroke. The quest to restore the neural connections in the brain has been spurred by two recent scientific developments. One was the isolation of so-called stem cells, the primordial cells from which all others evolve, that can potentially be made into neural cells for transplantation. In addition, in tests conducted in animals, the cells have had the ability to migrate through the brain to where they are needed to repair damage. A second development was the discovery that adult brains continue to produce new cells, overturning conventional wisdom that brain cells are not replenished. This suggests some capacity for nervous system regeneration. The discoveries have set off a race by companies hoping to develop cells to be sold for neural transplantation, part of the larger field of regenerative medicine. But harnessing such cells will require negotiating a minefield not only of technical challenges but of ethical ones, since most stem cells come from either embryos discarded by fertility clinics or aborted fetuses. Some scientists and business executives worry that the neural implant field will repeat the history of gene therapy, which has gone through 10 years of largely dashed hopes, controversial clinical trials and burned investors, though there have been some recent signs of success. "We would do well to learn the lesson from the troubled path of the gene therapy field: not to promise too much too early," wrote Anders Bjorklund and Olle Lindvall, Swedish scientists, in a commentary in the June issue of Nature Neuroscience. They said they see signs of a rush toward "ill-founded clinical trials" without adequate scientific rationale. Still, the two scientists have been implanting brain tissue from aborted human fetuses into the brains of people with Parkinson's disease, which causes a loss of motor skills, for almost a decade. In some patients the treatment has caused a slight improvement in motor control, which has lasted 5 to 10 years. But such treatment, which has also been done in this country, requires several fetuses for each patient. Moral questions notwithstanding, there are simply not enough fetuses to treat this nation's million or more Parkinson's patients. So scientists are searching for cells that can be mass produced -- "neurons in a bottle," said George W. Dunbar Jr., acting chief executive officer of StemCells Inc., in Sunnyvale, Calif., one of the companies pursuing the treatments. The cells implanted in Mrs. Elam were supplied by Layton BioScience Inc., also of Sunnyvale, and derived from testicular cancer cells isolated from a patient in the 1970's. Scientists found, almost serendipitously, that when treated with chemicals called retinoids, some of the cells turned into neural cells. Six of the 12 stroke patients treated with the cells had some improvement in motor skills, said Dr. John Kondziolka, the University of Pittsburgh neurosurgeon who performed the operations. Similar hints of success have been found in clinical trials run by Diacrin Inc. of Charlestown, Mass., the company furthest along in neural cell implants. It harvests brain cells from pig fetuses, which have been used to treat more than 20 Parkinson's patients and several with stroke, Huntington's disease and epilepsy. But there are fears the cancer-derived cells could cause cancer and that cells from pigs could infect patients with animal viruses. Diacrin recently suspended its trials on stroke victims after two of five patients suffered seizures, though the company does not think the pig cells were the cause. While Layton and Diacrin say their cells are safe, some experts think they will eventually be replaced by alternatives that are less unappealing to patients. That would mean human stem cells, which can be grown in great quantities. The greatest excitement revolves around so-called embryonic stem cells, which were first isolated in 1998 by Dr. James Thomson of the University of Wisconsin. These cells can turn into virtually any cell in the body -- including the liver, kidney, blood or heart, as well as neurons. But such cells are at the center of an ethical controversy, with opponents saying it is immoral to use embryos for medical purposes. By law, federal money cannot be used for research involving the destruction of embryos. The National Institutes of Health has proposed new guidelines to allow scientists receiving its money to work with the cells, provided that the cells are created with private money. Senators Arlen Specter, Republican of Pennsylvania, and Tom Harkin, Democrat of Iowa, have proposed a bill that would ease the restrictions. But abortion opponents remain opposed to any such relaxation. The research ban does not affect scientists with corporate financing, which has allowed companies to dominate the field. Geron Corporation of Menlo Park, Calif., which financed the work at Wisconsin, has commercial rights to the embryonic stem cells. It also has the patent rights to a similar type of primordial cell isolated by Dr. John Gearhart of Johns Hopkins University, also with Geron financing. Other companies, looking to sidestep both Geron's patents and the ethical issues surrounding embryonic cells, are using so-called neural stem cells on which they have obtained patents. These are less versatile than embryonic stem cells. They can turn into different types of neural cells but probably not into others, like kidney or liver cells. But those working with neural stem cells say that might even be an advantage for treating a neurological disease. Embryonic stem cells "turn into bone cells and knee cells," said I. Richard Garr, president and chief executive of NeuralStem Biopharmaceuticals Ltd. of College Park, Md. "You can't put them in a person's head without being 100 percent sure they won't turn into these other things." Dr. Thomas B. Okarma, president and chief executive of Geron, countered that embryonic cells could more easily be multiplied and made to live forever than the neural stem cells, providing an endless supply. "The more upstream you start, the more total control," he said. In neural stem cells, NeuralStem is competing with StemCells Inc., a publicly traded company that was known as CytoTherapeutics Inc. until it abandoned its previous business to focus on stem cells. Layton, which made the cells used on Mrs. Elam, has now also moved into neural stem cells by obtaining from Children's Hospital in Boston a license for a line of cells developed by Dr. Snyder. The other companies also have strong scientific credentials. NeuralStem was founded by scientists from the National Institutes of Health laboratory of Dr. Ronald McKay, a pioneer in neural stem cells. StemCells counts among its scientific advisers Dr. Irving L. Weissman, a stem cell expert at Stanford, and Dr. Fred H. Gage of the Salk Institute for Biological Sciences, who made some of the crucial discoveries that the adult brain can grow new cells. Other companies in the emerging field include ReNeuron Ltd. in London and Neuronyx of Malvern, Pa., which is headed by Hubert Schoemaker, the former chief executive of Centocor, a leading biotechnology company now owned by Johnson & Johnson. The neural stem cells are not free of ethical controversy, since they generally come from fetuses. But the companies say that since they can multiply the cells in the laboratory, they might need only a single fetus to supply hundreds of patients, if not the entire world demand. "If we had to go back to human fetal material on a continuing basis, that would be a concern," said Gary L. Snabel, president and chief executive of Layton. But with only a few fetuses needed for all time, "most people would say that's not an unreasonable strategy." The recent discoveries that adult brains still contain some stem cells makes it possible to derive such cells from adults, which would remove the ethical questions. But the scientists say the fetal cells are easier to obtain and easier to grow and that adult stem cells might lack the resiliency of the embryonic or fetal ones. There are still many technical problems to overcome with both neural stem cells and embryonic stem cells, and it could be several years before clinical trials begin. The biggest challenge is trying to get the stem cells to reliably turn into a single desired type of cell, which is usually done by exposing the cells to certain growth factors or implanting particular genes in them. This cannot be done yet for embryonic stem cells, though there has been progress. Dr. McKay of the health institutes has turned mouse embryonic stem cells into neural cells that produce dopamine, the chemical lacking in patients with Parkinson's. Another approach is to use drugs to try to stimulate the brain to grow its own new cells. Harry M. Tracy, publisher of Neuroinvestment, an investment newsletter in Rye, N.H., that follows the neurological medicine companies, said some of the drugs might reach the market before stem cell implants. Still, he said, a combination of both approaches would probably be needed. Rebuilding With Stem Cells Stem cells, the master cells from which all other cells in the body develop, might be used to replenish many other tissues. Companies are trying to harness the cells to rebuild hearts, bone, blood and other tissues, part of a field coming to be called regenerative medicine. At the Geron Corporation of Menlo Park, Calif., scientists have already turned embryonic stem cells into heart muscle cells that spontaneously beat in the test tube. Studies in mice have shown these cells integrate into the heart. Such stem cell therapy might be used to rebuild hearts after a heart attack, since heart muscles do not regenerate after being killed. Osiris Therapeutics of Baltimore is starting clinical trials to see if stem cells can be used to regrow bone. It is using mesynchymal stem cells, which turn into the body's connective tissue, like bones, cartilage, tendons and bone marrow. The biggest existing use of stem cells is for bone marrow transplants to replenish the body's immune system. This works because the marrow is rich in hematopoietic stem cells, which turn into blood cells. Some companies are trying to make a business of technology that can be used in stem cell therapy. Aastrom Biosciences of Ann Arbor, Mich., has a device that can multiply cells, including stem cells. Nexell Therapeutics of Irvine, Calif., also has techniques for separating and growing cells. Its device was used to multiply cells used recently in what is considered the world's first gene therapy success: French scientists' treatment of three girls with a rare immune disease. Ariad Pharmaceuticals of Cambridge, Mass., recently published a scientific paper about technology it developed that could help control the growth and differentiation of stem cells. Other uses of stem cells could provide income before cell transplants become feasible. Geron expects its first stem cell profits to come from making liver cells that pharmaceutical companies can use to test how well a drug is metabolized by the liver and whether the drug causes liver toxicity. NeuralStem Biopharmaceuticals has signed an agreement with Gene Logic, a genomics company, to use the stem cells to help define the functions of genes. By ANDREW POLLACK Copyright 2000 The New York Times Company http://www.nytimes.com/library/national/science/053000sci-stem-cells.html janet paterson 53 now / 41 dx / 37 onset 613 256 8340 / PO Box 171 Almonte Ontario K0A 1A0 Canada visit my website "a new voice" at: http://www.geocities.com/janet313/