St. Louis -- The W. M. Keck Foundation of Los Angeles has awarded $900,000 to Washington University School of Medicine in St. Louis for research on repairing the injured spinal cord. Dennis W. Choi, M.D., Ph.D., the Andrew B. and Gretchen P. Jones Professor of Neurology and head of the Department of Neurology, will lead the project.
The grant will support pioneering work on spinal cord transplantation. The long-term goal is to use cells derived from embryonic cells to replace lost tissue. Such transplants might enable the cord to function once more so patients could regain bladder and bowel control. Perhaps they might one day result in enough regeneration for people to walk once more.
"We are very pleased that the Keck Foundation has seen the enormous potential of this work and is willing to fund it in its early stages," says William A. Peck, M.D., executive vice chancellor for medical affairs at the University and dean of the School of Medicine. "We believe that Washington University, with its long tradition of neuroscience, neurosurgery and rehabilitation research, will become one of the leading spinal cord injury centers in the world."
More than 500,000 Americans are paralyzed from injury to the spinal cord, and there are about 20,000 new injuries each year. "The time is right for us to focus our attention on this terrible problem, both because of the human toll it exacts and because science has brought us to the point where a solution is possible," Choi says.
Because the spinal cord does not repair itself, the best hope for restoring lost functions lies in replacing lost tissue. Fetal cells have been used in animals, but ethical concerns and the limited availability of such cells limit practical application in humans. "We feel that embryonic stem cells may be the best source of cells to replenish cells lost from the spinal cord," says John McDonald, M.D., Ph.D., assistant professor of neurology and director of the medical center's new Spinal Cord Injury Unit.
Over the past two years, McDonald, Choi and David I. Gottlieb, Ph.D., professor of neurobiology and associate professor of biochemistry and biophysics, have conducted the initial studies that led to the current project. The pioneering work showed that cultured rodent embryonic stem cells can be chemically instructed to develop into nerve cell precursors suitable for transplantation into the injured spinal cord.
Embryonic stem cells are the raw material of the body, able to develop into all of the cell types needed to make a human being. Because they can reproduce themselves indefinitely, a single cell line theoretically could provide transplants for many patients. Therefore, a continual source of embryos would not be required.
Embryonic stem cells also are very amenable to genetic modification, so they could carry genes that would make a transplant more likely to succeed. Combining genetic modification with transplantation will be one of the novel features of the current project, which will explore ways to enhance the survival and functioning of precursor cell transplants.
Twelve faculty members will conduct four studies. Two studies will focus on processes that would sabotage spinal cord transplants if precautionary measures were not taken. Choi will study excitotoxicity, a process that quickly kills nerve cells by overstimulating them with chemicals they normally respond to. "Our preliminary research suggests that nerve cell precursors are sensitive to a chemical called glutamate," says Choi. "So drugs that block glutamate's action might protect transplanted cells from excitotoxic damage."
Eugene M. Johnson Jr., Ph.D., will explore factors that induce programmed cell death or apoptosis in nerve cell precursors, destroying them over days or weeks. "Knowledge of the extent and mechanisms of apoptosis in these cells at various stages of development will provide the information we need to design appropriate pharmacological and genetic strategies to prevent such death," Johnson says. He is the Norman J. Stupp Professor of Neurology, professor of molecular biology and pharmacology and co-director of the Alzheimer's Disease Research Center.
McDonald will apply insights from these two projects to transplantation studies, again using rats. "We will determine whether interventions that enhance the survival of cultured embryonic stem cells also promote the survival of the cells after transplantation," he says. "Then we will determine whether increased survival translates into enhanced function." By using specific labeling methods, the researchers will distinguish transplanted cells from host cells and determine how far they have migrated or sent projections from the transplant site.
In the fourth project, Mark F. Jacquin, Ph.D., research professor of neurology, and colleagues will use anatomical and physiological methods to determine whether cell transplantation restores electrical circuits from the injured part of the spinal cord. They also will find out whether the transplanted cells must integrate themselves into these circuits for functional recovery to occur. "This study will determine whether transplanted nerve cell precursors can function as well as survive," Jacquin says.
Gottlieb, David Gutmann, M.D., Ph.D., associate professor of neurology, genetics and pediatrics, and Chung Hsu, M.D., Ph.D., professor of neurology, also are co-investigators. Hsu will oversee studies of functional changes after transplantation, whereas Gottlieb and Gutmann will genetically engineer the transplantable cells. "We hope our work will offer a new paradigm for how best to use embryonic stem cells for transplantation," Gottlieb says. "Our aim is to advance the science of embryonic stem cell genetic engineering to make it much more efficient and accessible."
The researchers see applications of their work to many neurological conditions. "The need to promote recovery of function is common to all diseases that damage the brain and spinal cord," Choi says. "Developing treatments to help people who already have sustained damage to the central nervous system is a great frontier in clinical neurology and neurosurgery."
The W. M. Keck Foundation is one of the nation's largest philanthropic organizations. Established in 1954 by the late William Myron Keck, founder of The Superior Oil Company, the Foundation's grantmaking is focused primarily on the areas of medical research, science, and engineering. The Foundation also maintains a program for liberal arts colleges and a Southern California Grant Program that provides support in the areas of civic and community services, health care and hospitals, precollegiate education and the arts.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC Health System.