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Teaching the Body to Heal Itself November 7, 2000 - In the Star Trek movie "The Voyage Home," about a visit to present-day Earth from the future, Dr. McCoy sneaks into a hospital to rescue the injured Chekov and views with horror the barbarous implements of 20th-century medicine, the gross knives and saws so unsuited for the delicate soft machinery they are intended to repair. With the new tools of genomics and stem cell biology, some biologists hope to develop a set of novel treatments that may not seem so alien to visitors from three centuries ahead. "Regenerative medicine," as some call it, would depend not on scalpels and poisons but on the same agents the body itself uses to repair its own fabric — cells and chemical signals. Medicine has long made use of the body's own healing powers. Vaccines, for example, one of the oldest and most effective tools at the physician's disposal, work by priming the immune system. But regenerative medicine is not just more of the same. Its advocates aspire to a higher goal than traditional medicine: not just to patch up the body's failing systems, but to make them as good as new. Medical treatments available today, especially for the degenerative diseases of age, generally help patients get along with failing hearts or arthritic joints but do not make whole the underlying damage. Regenerative medicine, its proponents say, will provide youthful tissues in place of those that are old or damaged. "When we know, in effect, what our cells know, health care will be revolutionized, giving birth to regenerative medicine — ultimately including the prolongation of life by regenerating our aging bodies with younger cells," said Dr. William Haseltine, chief executive of Human Genome Sciences. Dr. Thomas Okarma, president of the Geron Corporation, calls regenerative medicine a "new therapeutic paradigm" which will lead to patients' returning from the hospital with new tissues and organs, just as a car returns from the auto shop with new parts in place of the defective ones. "We are trying to understand the wisdom of nature and harness that in creative ways," Dr. Okarma said. Dr. Ronald McKay, an expert on neural stem cells at the National Institutes of Health, believes the body's tissues are "self-assembling," once their source or stem cells are given the right cues. "I don't know how to make a heart," Dr. McKay said. "But once you know how to take stem cells and turn them into heart muscle, it's easy." "In a few months it will be clear that stem cells will regenerate tissues," Dr. McKay said. "In two years, people will routinely be reconstituting liver, regenerating heart, routinely building pancreatic islets, routinely putting cells into brain that get incorporated into the normal circuitry. They will routinely be rebuilding all tissues." Scientists are not known for pessimism about the likely effects of their discoveries, and commercial enterprises rarely understate the possible benefits of their proprietary knowledge. For now, regenerative medicine is merely a concept. Still, there is substance behind the optimistic predictions. In recent years, scientists in the public and private sectors have made several notable advances in understanding how the body repairs itself, particularly in the fields of signaling systems and stem cells. Perhaps nearest to fruition is work on the body's cell-to-cell signaling system. The body's 100 trillion cells govern themselves through an exchange of chemical signals. Cells secrete chemical signals to influence the behavior of other cells, and they receive signals through special receptors embedded in their surfaces. Until recently, only a handful of these signals had been identified, like the interleukins produced by the white blood cells and erythropoietin, the blood cell-stimulating protein that has created a fortune for Amgen. But Dr. Haseltine has asserted for several years that the entire communications system of the human body, a set of some 11,000 signaling factors and their receptors, has been identified and captured by Human Genome Sciences. This remarkable claim has been generally ignored or disbelieved by academic biologists because it has not been reported in scientific journals. But the claim is garnering credibility because Human Genome Sciences has applied for 9,200 patents on the genes involved in the human cell communication system and has been granted United States patents on 146; it has built a plant to manufacture these factors, and it has advanced four of them to clinical trials. None of these factors have yet reached the stage of being approved by the Food and Drug Administration. But this first crop of new factors, if their trials prove successful, demonstrate the possible scope of regenerative medicine. One, for example, known as keratinocyte growth factor 2, is a protein that stimulates the cells of the skin and inner body linings to heal wounds, and is being tested on patients with nonhealing ulcers. Another, B-lymphocyte stimulator protein, is a major player in the body's immune system. Human Genome Sciences plans to try it on patients with defective immune systems and to test a drug that suppresses the protein in patients with lupus, an autoimmune disease where the protein is overactive. Discovery by ZIP Code The normal route to finding new human genes, as promised by sequencers of the genome, is to hunt them down in the raw DNA sequence, a challenge considering that genes make up only 3 percent of the genome. Human Genome Sciences has discovered its factors in a quite different way that, despite the company's name, does not depend on knowledge of the full human genome sequence at all. The company's method depends on the fact that a cell regularly makes copies of the genes whose products it needs. These gene transcripts, known to biologists as messenger- RNA's, can be captured and analyzed before the cell degrades them. But the transcript capture method has long been viewed as most likely to give a very incomplete picture of the human gene repertoire, because many transcripts are made rarely and in minute quantities by specialized cells. Dr. Haseltine said his company had overcome this limitation, in part by capturing gene transcripts from many different cell types, including those from fetal tissues and organs at various stages of development and from different kinds of tumor cell. He has found evidence, he says, for 140,000 human genes, far more than the number predicted by the usual gene-finding computer programs that analyze the DNA sequence for likely genes. From these 140,000 genes, Human Genome Sciences has been able to identify those that make signals and receptors because all these genes have a hallmark sequence of DNA letters. The sequence specifies a sort of ZIP code that is built into the structure of each protein produced by those genes. The ZIP code directs the cell to export the protein. It is found both in the signal proteins that are sent out by the cell and in the receptor proteins, which are half-exported and then embedded in the cell's outer membrane. With the sequence of 140,000 human genes in hand, Dr. Haseltine set his computers to look for all genes carrying the export ZIP code. Out fell some 11,000 genes, the working parts of the body's cell-to-cell communications system. Dr. Haseltine's achievement has been overshadowed by the genome- decoding success of his former colleague, Dr. J. Craig Venter, now president of the Celera Corporation, and by other biologists' uncertainty as to the standing of his unpublished claim. But if his assertion is true, he has pulled off a remarkable feat. Dr. Gưnther Blobel of Rockefeller University, who won a Nobel Prize last year for discovering in the 1970's the cell's general system of ZIP code sorting, said that he could not verify Dr. Haseltine's claim, but that it was quite possible. And, he said, the number of signaling factors sounded about right, although some might have been missed. "Absolutely, he is on to something, there is no doubt about that," Dr. Blobel said. Dr. Haseltine's company has developed a systematic way of testing its signaling factors to see which may make useful drugs. Human Genome Sciences has synthesized all the genes and used the genes to manufacture samples of all 11,000 signaling proteins. To find a protein that makes the T cells of the immune system grow, for example, Human Genome Sciences cultures batteries of human T cells in laboratory glassware and exposes them to each of the 11,000 proteins to see which has the desired effect. If several proteins affect a target cell, the company can screen for the one that is most specific, rejecting proteins whose other actions could cause side effects. Regenerative Medicine Sitting in the conference room of Human Genome Sciences' art poster-strewn headquarters in Rockville, Md., Dr. Haseltine said the concept of regenerative medicine grew out of the company's drug development strategy. His first thought had been to look among the genes discovered by the transcript-capture method for any that were similar to already known growth and repair factors, and that might serve as novel drugs. But in testing his gene products systematically on various types of human cell, Dr. Haseltine said, he became interested "in the broader concept of regulating cell behavior and drawing on the ability of the body to build any tissue from a fertilized egg." "We are a self-assembling organism," he said. "That information is there to be captured and used. If we have all the genes, we can find which gene creates the desired medical response in a cell." He first described his concept of regenerative medicine in a speech in 1998, though others have used the phrase independently. "It's a fundamental principle of regenerative medicine that we only have to trigger the body to do what it needs to do," Dr. Haseltine said. But if the body has all these repair systems in place, and the existing signal system fails to work, why should adding more signals in the form of a drug make any difference? Dr. Haseltine suggests that evolution has had to make a trade-off in longer-lived animals, banking down their tissues' regenerative abilities in order to erect higher barriers against cancer. He noted that rats, which generally do not live long enough to develop cancer, can recover from wounds that would kill a person. Giving patients extra doses of the right signals should enable human tissues to unlock their latent regenerative abilities, he said. continued in part two ... 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