Replacement organs grown in the lab. Cancer vanquished. The ravages of time reversed. Researchers now think it's more a question of "when" rather than "if"
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Hidden in the nooks and crannies of our brains, bone marrow, and hair follicles are small numbers of nearly immortal cells that repair damage and constantly rejuvenate our bodies. These diligent menders, known as adult stem cells because other cells seem to stem from them, can migrate wherever they are needed and multiply into armies of new cells to form skin and bone, blood or brain.
A spate of recent discoveries has buoyed scientists' hopes that it will soon be possible to harness these powerful allies and usher in a new era of medicine. Results from animal tests suggest the regenerative power of stem cells may soon be turned into treatments for a range of human ills -- from strokes and diabetes to Alzheimer's and Parkinson's diseases, heart attacks, cancer, and spinal-cord injuries. Stem cells may also be able to repair damaged organs, such as the liver. One day, they may even be coaxed into growing into entire organs that could be used as human replacement parts.
The pace of research is especially surprising considering that, while their presence had been long suspected, no one had ever actually seen a stem cell until two years ago. Bone-marrow transplants, for example, had demonstrated that marrow contains cells that can produce all the various types of red and white blood cells. And the single cell that begins to divide when an egg is fertilized manages to differentiate into all the organs, tissues, and systems needed to form an entire organism. So scientists figured that an extraordinary cellular process was at work.
THE BREAKTHROUGH. Then, in late 1998, two teams of scientists -- one headed by John Gearhart of Johns Hopkins University, the other by James Thomson of the University of Wisconsin-Madison -- isolated these elusive cells from human embryos and managed to grow them in the laboratory. These master cells, with the capability to become any cell, tissue, or organ in the body, are created at the moment of conception, or almost immediately thereafter. From them, in a mere nine months, springs a complete human being.
The discovery of stem cells created a scientific sensation -- and an immediate controversy, not least because the cells fell under a ban that prohibited federal funds from being used for research involving human fetal tissue. Meanwhile, researchers quickly found the adult body has reservoirs of more specialized stem cells that can divide to form into groups of cells. Those cells dedicated to forming nerves live in the ventricles of the brain, while stem cells for blood and bone reside in our bone marrow. Just recently, researchers from the University of Pennsylvania Medical Center and New York University School of Medicine discovered stem cells in lumps at the base of human hair follicles that appear to form new skin and heal wounds.
While many types of cells in the body can divide, these common cells merely produce two identical cells that are the same "age" as the original. Governed by a biological clock, they will divide only a preprogrammed number of times in a typical individual's lifetime. But when stem cells divide, they not only produce the sort of cell that is called for -- be it a heart muscle or a nerve -- but another stem cell as well. Moreover, the new, replacement cell is the same age as if it had been taken from a newborn.
Today, stem-cell research is being spearheaded mostly by private companies, especially those aiming to find ways to prolong life and blunt the effects of aging -- a new discipline that has come to be called "regenerative medicine." Geron Corp. (GERN
), which is listed on the Nasdaq, is in the lead, but a small cadre of new startups are also jumping in (see BW Online, 10/27/00, "A Bold Biotech Play for the Extremely Patient").
FROM MAN TO SHEEP. The adult or "multipotent" stem cells are proving to be more versatile than anyone imagined just a year ago. To see how one type of stem cells functions in the body, a group of researchers from The Children's Hospital of Philadelphia and Osiris Therapeutics Inc., a Baltimore regenerative-medicine startup, transplanted adult stem cells from human bone marrow into fetal sheep. Because the tissues that grew out of the stem cells had human DNA, researchers were able to identify them in the mature animals.
The group reported in the November issue of Nature Medicine that the human stem cells continued to thrive in the sheep for more than a year. Moreover, they had become cells in skeletal muscle, heart muscle, bone, cartilage, the thymus gland, and stroma, which is the supporting structure for bone marrow. In addition, the human transplants were found at the clipped stumps of the animals' tails -- an indication that stem cells may also play a role in healing wounds.
The findings seem to indicate that stem cells know where they must go to work. "The transplanted cells migrated to different parts of the sheep's body and differentiated into types of tissue present at each site," says Alan W. Flake, director of The Children's Institute for Surgical Science at The Children's Hospital, who headed the study.
Another surprise was that the cells weren't rejected by the sheep's immune systems -- even when transplantation took place after the animals' immune systems were already functioning. "These cells may have special properties that may allow transplantation between individuals, or even species, without rejection," notes Flake.
Of course, study supporter Osiris Therapeutics -- named for the ancient Egyptian god of the afterlife -- has its eye on some commercial products. It is already conducting clinical tests of a stem-cell cocktail that is hoped will speed recovery of bone-marrow transplant patients, and it's also developing stem-cell infusions aimed at rebuilding aging bones and repairing damaged cartilage.
Indeed, marrow stem cells are proving to have capabilities that go beyond blood and bone. Last summer, a team of scientists from Yale University and New York University offered apparent proof that stem cells from bone marrow could regenerate human liver cells. The investigators, who reported their findings in the July issue of Hepatology, analyzed liver samples from female leukemia patients who had undergone bone-marrow transplantation from a male donor, and those from male patients who received a liver transplant from female donors.
TESTS AND TRIUMPHS. Telltale cells, containing the XX and XY chromosomes that indicate the opposite sex, showed up in the livers of all patients. "Furthermore, we're talking about significant amounts of functional liver tissue -- up to 40% in one case we studied," says Neil Theise, associate professor of pathology at NYU School of Medicine and lead author of the study. Theise says the technique already has been demonstrated in mice by scientists at StemCells California Inc., (STEM
) a research company based in Sunnyvale.
Finding ways to use stem cells to repair human livers is also the goal of Incara Pharmaceuticals Corp. (INCR
), a startup in Research Triangle, N.C., that is supporting researchers at the University of North Carolina at the Chapel Hill School of Medicine. The scientists, Lola Reid and Hiroshi Kubota, reported in the November issue of the Proceedings of the National Academy of Sciences that they had isolated stem cells specific to producing liver cells and had demonstrated that a single cell placed in a culture would rapidly proliferate. "We are the first to have conditions in which a single cell can be put in, and it will survive and grow extensively," says Reid.
Even though the experiment was conducted with animal cells, it produced just the result that Incara was hoping for. There are now 15,700 patients awaiting liver transplants in the U.S., but only 4,000 liver transplants have been performed. "We believe that if transplanted liver stem cells can expand and differentiate in a patient with liver disease as well as they do in culture, they might provide a lifesaving alternative to whole-liver transplants," says Incara CEO Clayton Duncan.
Reid recently won a U.S. patent on the process and has licensed it to Incara, where she serves as chief scientist. Next year, the company plans to begin clinical trials by treating children with genetic liver diseases, as well as adults suffering from chronic liver failure, with transfusions of human stem cells.
FIXING A BROKEN HEART. The stem cells found in bone marrow may also hold the key to rejuvenating ailing hearts, Ray C. J. Chiu, a professor of cardiothoracic surgery at McGill University Health Center in Montreal, told the annual meeting of the American Heart Assn. in November. When Chiu and his colleagues injected a type of stem cell -- called stromal cells and isolated from bone marrow -- into the hearts of rats, the cells differentiated into new heart muscle in 20 out of 22 of the animals. Moreover, the new cells seemed to have made the connections to nearby cells that allow them to beat in unison.
"Heart failure is the death of functioning heart muscle," says senior author Chiu. "The goal of our study is to replace those dead cells with new heart-muscle cells. Marrow stromal cells are extremely promising."
Still, many of the experiments conducted with animals do not necessarily prove the new cells function like original ones. Most often, the presence of the new cells is determined by examining microscope slides of dead tissue. But some of the most encouraging indications that they do indeed behave like original ones were presented at the meeting of The Society for Neuroscience in early November.
Earlier research had demonstrated that new nerve cells could be encouraged to grow. But some scientists were doubtful they could hook into the nervous system and connect to the brain. But at the society's conference in New Orleans, a research team from Johns Hopkins University announced that it had been able to restore movement to paralyzed mice by injecting into the animals' spinal fluid stem cells that control nerve development.
In the experiment, mice were infected with a virus that attacks the motor nerves in the spinal cord and left the animals dragging their hind feet. The investigators injected stem cells into the base of the spinal cords of 18 mice. Within several weeks, about 5% to 7% of the cells had migrated to the region of the spinal cord that contains motor nerves and had become functional nerve cells. Fifty percent of the treated rodents regained the ability to place the soles of one or both of their hind feet on the ground.
PREPARING FOR HUMAN TESTS. The findings have implications for treating paralyzing motor neuron diseases, such as amyotrophic lateral sclerosis (ALS) and spinal motor atrophy (SMA). An inherited and common cause of infant death, SMA affects between 1 in 6,000 and 1 in 20,000 infants. ALS, which leads to fatal paralysis, affects as many as 20,000 people in U.S. Now, researchers anticipate human tests in the relatively near future. "Under the best research circumstances," says researcher Jeffrey Rothstein, "stem cells could be used in early clinical trials within two years."
Similarly, if neural stem cells transplanted into the eye also link to the optic nerve, they may one day be used to treat people whose vision has been impaired by retinal damage caused by diseases such as macular degeneration, glaucoma, retinal detachment, and diabetic retinopathy. In September, a team headed by Michael Young, assistant scientist at The Schepens Eye Research Institute, reported in Molecular and Cellular Neuroscience that neural stem cells injected into the eyes of rats with diseased retinas migrated to the right place, differentiated into the right types of cells -- and seemed to be in the process of establishing connections between the retina and the brain. "This is very encouraging," notes Young, who cautions that human treatment is still a long way off. "First we need to show that this can actually restore sight," he says.
The biggest mystery still facing stem-cell researchers is what makes stem cells "switch on" to form a certain kind of tissue. Whether they are found in the brain, bone marrow or hair follicles, all seem to possess the ability to form unexpected types of cells. Last summer, for example, scientists from the Karolinska Institute in Stockholm demonstrated that stem cells taken from the brains of adult mice and injected into both fertilized chicken eggs and mouse embryos were nurtured into heart, liver, muscle, and other tissues in both species.
Some kind of signal must trigger them to form the right cells in the right place at the right time. So far, the evidence seems to point to the proximity of injured or dying cells to healthy ones. When The Schepens Eye Research Institute's Young injected stem sells into the eyes of rats with healthy retinas, nothing happened.
VISION OF THE FUTURE. "These cells somehow sense that they are needed and begin to differentiate into cells that could take on the job of retinal neurons," Young says. Johns Hopkins neurologist Douglas Kerr made similar observations in his study of paralyzed mice. "Add these cells to a normal rat or mouse, and nothing migrates to the spinal cord," he says. "Something about cell death is apparently a potent stimulus for stem-cell migration."
Other researchers are beginning to probe the chemical factors that must direct stem-cell differentiation. Teams headed by Howard Hughes Medical Institute investigator Douglas A. Melton and Hebrew University geneticist Nissim Benvenisty tried to determine how growth factors might direct the earliest development of a human embryo. "Until now, no one had reported extensive and systematic studies on human embryonic stem cells," says Melton, who is at Harvard University.
In October, they reported in Proceedings of the National Academy of Sciences the results of exposing human embryonic stem cells to eight growth factors, an experiment undertaken in the hope of seeing what directs the first wave of cell division. The growth factors directed the stem cells to differentiate into three different categories -- endodermal, ectodermal, and mesodermal. Each of these later gives rise to various groups of cells that form organs and tissues.
The results were intriguing. Instead of causing the stem cells to form one type of cell, the effects were more subtle. One group of growth factors appeared to inhibit endodermal and ectodermal cells, but allowed differentiation into mesodermal cells. A second group induced differentiation into ectodermal and mesodermal cells, and a third group allowed differentiation into all three embryonic lineages.
The researchers believe their findings hint that telling a stem cell what to become will require that a combination of factors be present at the proper time. "It may be a bit like educating a child, in which you don't designate children in kindergarten as doctors, lawyers, or surgeons, but you give them some kind of general education," says Melton. "And, as they progress and show an interest in a specific field, you give them a more specialized education."
A bonanza awaits those companies that can identify, and learn to control, the growth factors that direct a stem cell to form a heart cell -- or an entire heart. And they know exactly where to look -- somewhere in the vast skein of DNA that is the human genone.
TURNING BACK THE CLOCK. Human Genome Sciences (HGSI
) in Bethesda, Md., is probing various types of mature cells to isolate the substances they use to communicate through the body. The company claims it has identified more than 10,000 of these signaling factors, and it has won more than 150 patents. Many of these factors will have therapeutic value in their own right. For example, the company is now testing a factor that triggers wounds to heal. Others are likely to act directly on stem cells.
Meanwhile, Geron is trying to turn back the biological clock with an enzyme called telomerase, which can rebuild the genetic sequences that shorten due to the aging process. The Menlo Park (Calif.) company, which supported the research that led to the first isolation of a human embryonic stem cell, is also looking for ways to drive a patient's adult stem cells back to the embryonic stage so that they can be directed to produce replacement tissues.
Adult stem cells are almost certain to be put to work rebuilding hearts, nerves, and livers before they are completely understood -- probably in the next few years. But the real reward will come when the complex chemical signals that drive their differentiation are deciphered. Only then will medicine be truly able to sculpt those cells that have been called the clay of life.
By Alan Hall in New York Edited by Edited by Douglas Harbrecht
Copyright 2000, by The McGraw-Hill Companies Inc. All rights reserved.
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