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continued from part one: Embryonic Stem Cell Powers Cell-signaling factors play a vital role in the development of the body from a single egg and in guiding the emergence of the body's many different cell types, including the vital stem cells that repair adult tissues. But it is the stem cells that are the living clay from which the body is sculptured and repaired. Like clay, stem cells are dull and featureless. But they can morph into blood, skin, bone or any of the body's other replaceable tissues. And they retain the gift of self-renewal which, to curb the risk of cancer, is withdrawn from all the body's mature cells. Stem cells, when they divide, usually produce one mature cell and one stem cell, thus maintaining their population numbers; mature cells produce daughter cells identical to themselves and can divide only a limited number of times, if at all. Stem cells last a long time, though they are not immortal; mature cells cannot renew themselves. Physicians are already drawing on the power of stem cells in a limited way, as in bone marrow transplants for leukemia, which rely on the blood stem cells in the marrow to regenerate the body's red and white blood cells, and in skin grafts grown from a patient's cells. But these applications are just a foretaste of those that some researchers expect. In mice, where almost all stem cell technology is developed first, biologists reported this year that they had reversed insulin-dependent diabetes by implanting stem cells from the pancreas. Researchers have even learned how to replace the tissues that normally are not renewed, like heart muscle and the dopamine-producing cells of the brain that are lost in Parkinson's disease. But this alchemy requires a special class of stem cell known as embryonic stem cells. Embryonic stem cells are created in the very early embryo; from them, all the bodies' tissues and organs are generated. Once the body is formed, the embryonic stem cells disappear, leaving behind a few descendants to keep the body in good repair throughout its lifetime. These descendants, often called adult stem cells, apparently lack the embryonic stem cell's power of generating any and all of the body's tissues. Nor can they renew themselves indefinitely, as can embryonic stem cells grown in glassware. Biologists are exploring two separate ways of harnessing the regenerative powers of stem cells, one through embryonic stem cells and the other by using of adult stem cells. Each route has different advantages. Human embryonic stem cells carry an ethical burden in that they are derived by destroying an embryo, although one due to be discarded by the fertility clinic where it was created. The embryo at this stage has no fetuslike features; it is a microscopic sphere of cells that holds an inner clump of cells destined to form all the tissues of the embryo. These cells, grown in the laboratory for the first time in 1998, were approved for use by government-supported researchers in August after sustained opposition from opponents of abortion. The promise of embryonic stem cells is that in principle they can be coaxed to develop into any desired tissue. Researchers at Indiana University showed in 1996 that mouse embryonic stem cells could be nudged down the lineage that leads to heart muscle cells and implanted in mice, where they would graft themselves seamlessly into the animal's heart. Biologists at Geron, of Menlo Park, Calif. have succeeded in making human embryonic cells develop into heart muscle cells. The field of human embryonic stem cells is for the moment dominated by Geron, which, under its visionary founder Dr. Michael West, financed the research that led to the isolation of the cells. The company also controls two other pieces of biological wizardry. It has formed an alliance with PPL Therapeutics of Edinburgh, which has rights to the nuclear transfer techniques used to create the cloned sheep Dolly. And it owns the rights to a human protein called telomerase. Probably as an anticancer mechanism, cells possess a division- counter that forces them into senescence after they have divided about 50 times. Telomerase can confer the gift of immortality on cells because it sets their division counter back to zero. In the body, it is found in cells with a limitless ability to divide — egg and sperm cells, and cancer cells. In the pursuit of generating fully youthful replacement tissues to repair old bodies, Geron has three powerful techniques to bring to bear. One is to extract adult stem cells from the patient, immortalize them with telomerase and return a fully youthful cell infusion or tissue to the patient. Second, replacement tissues could be generated from human embryonic cells by driving them down the appropriate lineages with cytokines and other agents. Third, if such tissues prove too provocative to patients' immune systems, Geron is working on ways to generate embryonic cells from patients' own mature cells. The company hopes to identify factors that reprogram human cells back to the embryonic state. A patient could then be treated with tissues made from his or her own embryonic cells. Adult Stem Cells Meanwhile other biologists have been pursuing the study of adult stem cells. The cells have long defied discovery because they are very hard to distinguish from other cells and because they hide out in special sites, which are only now being identified. The source of the brain's stem cells was discovered only last year — in the lining of the brain's fluid-filled ventricles — and the skin stem cells' hideout was identified this August as a special pocket half-way up the root of the hair follicles that stud the skin. About 20 different types of adult stem cell have now been identified with varying degrees of confidence. In the body, each type seems dedicated to replenishing its own tissue: neural stem cells make new brain cells, bone marrow cells make only red and white blood cells. In laboratory experiments, however, several types of adult stem cells seem able to take on other types' roles; perhaps, with the right signals, an adult stem cell will repair any tissue, not just its own. The degree of versatility of adult stem cells may prove an important clinical issue because bone marrow stem cells, for example, are easier to harvest from a patient than neural stem cells, and might in that case prove a preferable source of cells to treat, say, Parkinson's disease. Treating patients with cells derived from their own stem cells would avoid any problems of immune rejection. But adult stem cells can divide only a finite number of times and in older or diseased patients may have a limited lifetime left. Embryonic cells, however, have their division timers set back to zero. Tissues derived from them would be perhaps healthier and certainly more youthful than the patient's own. Their possible drawback is that of being rejected by the patient's immune system. But embryonic stem cells and adult stem cells seem much less provocative to the immune system than mature cells, so the risk of rejection may be minimal. One of the most intriguing aspects of stem cells is their ability to integrate themselves into target tissues and turn into cells of the right type. This property, known as engraftment, holds out the possibility that stem cells can be put to therapeutic use long before their behavior is fully understood. On the harbor waterfront in Baltimore, in a building that was once a tuna cannery, a company called Osiris Therapeutics — after the ancient Egyptian god of regeneration and immortality — is working to unlock the restorative powers of a special kind of adult stem cell. Called bone marrow stromal cells by some biologists and mesenchymal stem cells by Osiris, these obscure cells serve as the glue that keeps the body together because they repair the connective tissues of bone, tendon, cartilage and muscle. The cells also make the stroma, or support, on which the blood- forming cells of the bone marrow grow. Osiris's probable first product, now in clinical trials, is an infusion of mesenchymal stem cells for patients undergoing bone marrow transplants. The mesenchymal stem cells find their way to the bone marrow and build stroma, enabling patients to return home several days earlier than otherwise. Mesenchymal cells grown in glassware can be induced to develop into different types of mature cell. Cultured on bone material, they will form bone cells; in a gel, they grow into cartilage-making cells. Osiris has a bone-making preparation of stem cells, Osteocel, in clinical trials, and is working with animals to develop cartilage-making cells for joint repair and heart muscle cells for heart attack victims. If mesenchymal stem cells prove as effective as hoped in repairing bone, tendon and cartilage, says the company's chief executive, Dr. Annemarie Moseley, "Patients in middle age would come in, before the degenerative process starts, and would get a cell or tissue implant, and degeneration of the structural elements would no longer be part of the aging process." Making Lives Longer Companies pursuing regenerative medicine in its various forms are reluctant to talk about extending the maximum human life span, a project that has acquired ill-repute in the past. "Our objective is to increase health span, not life span," said Dr. Okarma, Geron's chief executive. "Our hope would be that our children live a great fraction of their life in wellness," But Dr. Michael West, Geron's founder and now chief executive of Advanced Cell Technology, has always had the goal of longer life in mind. "When I hear critics saying they don't want to see life span extended, they are thinking about the old myth of Tithonus where people live longer in a decrepit state. That's not what we are talking about doing. As long as people are wanted and happy, I think it's a very noble goal and we should strive for that, and regenerative medicine is one of the means to achieve it." In the myth to which Dr. West refers, a Greek youth beloved by the goddess of the dawn made the error of asking her for gift of eternal life instead of eternal youth. Later, bowed by miseries of age to which death could not put a natural end, Tithonus begged her to withdraw her gift, something that even Greek gods could not do. She did, however, provide the apparent consolation of turning him into a grasshopper. Having learned the grasshopper lesson, the pioneers of regenerative medicine aspire to renew individual tissues, at least as their primary goal. Their concept is far from proved, but it rests on a set of interesting scientific advances, has attracted considerable investment and, just possibly, may one day revolutionize many areas of medicine. By NICHOLAS WADE Copyright 2000 The New York Times Company http://www.nytimes.com/2000/11/07/science/07MEDI.html janet paterson, an akinetic rigid subtype parkie 53 now /44 dx cd / 43 onset cd /41 dx pd / 37 onset pd TEL: 613 256 8340 URL: http://www.geocities.com/janet313/ EMAIL: [log in to unmask] SMAIL: POBox 171 Almonte Ontario K0A 1A0 Canada