November 7, 2000
Teaching the Body to Heal Itself
By NICHOLAS WADE
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. Gύnther 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.
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.
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.