Nov. 3, 2000 -- How close are researchers to solving the mysteries of paralysis? Close enough to believe it may happen, according to new research out of Johns Hopkins and other institutions around the country. In fact, through the use of what's called stem cells, scientists may be bearing down on treatments not only for some types of paralysis, but also for other conditions such as Parkinson's disease, stroke and traumatic brain injury.
Like a magician pulling a rabbit out of his hat, researchers are managing to rapidly generate large numbers of nerve cells -- neurons -- out of the most unlikely places, including adult bone marrow and even the brains of donors who have been dead for more than 20 hours. And if the cells can be shown to work in humans as they have in animals, they hold the promise for dramatic improvements of many conditions.
New research being unveiled this week at a meeting of neuroscientists in New Orleans show the many possible treatments that could be developed through the use of immature cells known as stem cells, which are now being coaxed in the lab to become different types of nerve cells. The process of causing a cell to mature into a specific type of cell is called differentiation.
Scientists at Johns Hopkins report, for instance, that they've restored movement of newly paralyzed mice and rats by injecting neural stem cells into the animals' spinal fluid. Fifty percent of these stem cell-treated rodents recovered the ability to place the soles of both or one of their hind feet on the ground.
Hopkins' researcher Jeffrey Rothstein, MD, PhD, says in a written statement that "this research may lead most immediately to improved treatments for patients with paralyzing motor neuron diseases such as amyotrophic lateral sclerosis [also called ALS or Lou Gehrig's disease] and another disorder, spinal motor atrophy."
These conditions are caused by disease and not injury. "Under the best research circumstances," Rothstein says, "stem cells could be used in early clinical trials within two years."
This is not the only advance being touted at the conference. Researchers admit to being both highly pleased and surprised by their ability to rapidly induce these cell changes.
"From multiple points of view it's extremely exciting when viewed from the bedside. When viewed from a basic science point of view of what we thought we knew about cell fates, cell commitment, and development, it's just as exciting," say Ira Black, MD, chairman of neuroscience at the Robert Wood Johnson Medical School in Piscataway, N.J.
In addition to providing investigators with new, potentially limitless sources of human stem cells, the discoveries promise to help stem-cell researchers steer their way around the roadblocks thrown in their paths by people who for religious or political reasons oppose the use of stem cells derived from human embryos.
There are, in fact, many different types of stem cells, representing various stages of cells taken from different parts of the body. Embryonic stem cells used in research are derived from embryos generated for the purpose of in vitro fertilization but never implanted. Although these embryos, more than 100,000 of which are currently in cold storage, are usually discarded, many anti-abortion rights activists are opposed to their use for scientific research, even when the ultimate goal is compassionate medical research.
In addition to embryonic stem cells, there are other types of stem cells that are derived from cells that have moved partway down the path to becoming a specific type of tissue, such as blood vessels, organs, or nerve cells.
As Black and colleagues show, they have been able to take stem cells from the bone marrow of adult rats and humans -- cells that are normally fated to grow into blood vessels and similar tissues -- and with a little manipulation in the laboratory convince them to turn into nerve cells instead. As if that trick weren't impressive enough, they've managed to do it in a matter of minutes or hours, rather than days or weeks as one might reasonably expect.
"There are a number of remarkable potential advantages," Black tells WebMD. "The cells grow remarkably quickly in culture, so that with a single bone marrow [collection] we can obtain a virtually limitless supply of cells. In addition, the accessibility certainly obviates the need to go into the brain ... [and] then obtain neural stem cells from deep within the cerebral hemisphere."
Not to be outdone, Fred H. Gage, PhD, and colleagues from the Salk Institute, Children's Hospital of Orange County and Stanford University, all in California, report that they were able to snatch adult rat and human nervous system stem cells from the jaws of death, get them to multiply, and turn into nerve cells -- even when the donor had been dead for more than 20 hours.
"We were able to induce some of the cells taken from the brains of cadavers to turn into neurons. The research shows that the tissue could be a new, noncontroversial source of human neural cells for transplantation and experimentation," says Gage in a written statement.
Researchers at the National Institute for Neurological Diseases and Stroke (NINDS) have also found it surprisingly easy to get nerve stem cells to do you what you want them to do. Ronald D. G. McKay, PhD, chief of the laboratory of molecular biology at NINDS and colleagues have been able to direct stem cells from mouse embryos to turn into one of two types of brain cells that are essential for normal function.
One type of cell they have been able to grow produces dopamine, a chemical that helps to control body movement and is largely absent in the brains of people with Parkinson's disease. The other type of cell produces serotonin, a hormone that helps to control mood; clinical depression can be caused by a defect in how the brain stores and uses serotonin.
"You have to know what you're doing, and the procedure takes about a month. You are mimicking a lot of steps in the differentiation that would normally happen [in real life], so you are coaxing the cells through an impressively complicated set of transitions. But the fact is that the conditions that we have apparently support that really quite efficiently," McKay tells WebMD.
Okay, so once you've got all these swell new stem cells, can they be used to possibly treat more than just ALS or spinal motor atrophy? Tracy McIntosh, PhD, and colleagues at the University of Pennsylvania and Harvard Medical School have an answer. They showed that stem cells from the brain, when transplanted into the brains of adult mice with traumatic brain injury, produced a dramatic improvement in their ability to control movement for up to 12 weeks after injection. But although the treated mice were better able to move, they did not show any improvement in their ability to learn or remember a new task following brain injury.
"We were targeting the motor cortex [the region of the brain that controls movement] for injection of the cells, although some of the cells did seem to migrate into the region that is responsible for controlling memory, which is the hippocampus, but I don't think that enough of them got there," McIntosh tells WebMD. "In the future we're going to try to inject cells directly into the hippocampus to see if we can get more cells integrated into that region." McIntosh is the Robert Groff Professor of neurosurgery and director of the Head Injury Center at the University of Pennsylvania in Philadelphia.
McIntosh's collaborator on that study, Evan Snyder, MD, PhD, and his colleague Seth Finkelstein, MD, PhD, show in a separate study that treatment combining nerve stem cells with a growth factor enhances recovery in rats with strokes caused by a blockage of blood flow in the brain. The combination of the growth factor and the stem cells produced greater improvements in treated animals than either agent given alone.
The rapid advances in stem cell research and treatments may even allow physicians to act more quickly and more effectively when someone comes into the emergency room suffering from stroke or head trauma, says Snyder, assistant professor of neurology at Harvard Medical School.
"The new approach I suspect is not going to be what you do now, which is you admit a patient with trauma or with a stroke and maybe [try to prevent inflammation], but basically you watch what happens with the injury over a period of time, and then after a week or two when you see what's left of the deficit, then you begin thinking about repair," Snyder tells WebMD. "I think what's going to start happening now is that when somebody comes in with a stroke, or head trauma or spinal cord injury, we're going to snap into action, probably within the first 24 to 48 hours, if not sooner, using growth factor therapy, cellular therapies, anti-[cell death] therapies in some kind of elegantly orchestrated manner yet to be determined. I think we're going to start doing intervention a lot earlier than we ever thought about before."