In the nine years since on-screen superhero Christopher Reeve tumbled from a horse and broke his neck, the field of spinal cord injury research has been all but transformed.
At the time of the actor's accident, embryonic stem-cell research wasn't yet a reality. Scientists didn't understand the immune system's role in spinal cord repair. And researchers hadn't identified a key protein that stops central nervous system cells from regenerating.
Fast forward to 2004, when paralyzed patients are more hopeful than ever that science will one day return what they have lost: the ability to walk.
And, for that, researchers largely credit the efforts of Reeve, who died of heart failure Sunday at 52.
He "was largely responsible for the reawakening of interest in spinal cord injury," said Dr. John A. Jane, chairman of the neurosurgery department at the University of Virginia, who treated Reeve and stabilized his injuries after the 1995 accident.
"One of the big things Chris did was get everyone to understand that this was a solvable problem - that it wasn't impossible," said Dr. John W. McDonald, who had treated the actor since 1999 in a rehabilitation program that achieved remarkable results. "I think that's where we stand now."
Reeve, whose title role in the Superman film series brought him stardom, became a tireless advocate for spinal injury research, using his fame and fortune to spotlight an injury that afflicts about 250,000 people in the United States.
Paralyzed from the neck down, Reeve defied conventional wisdom by making significant gains - he could move his fingers and toes, feel a pinprick practically anywhere and straighten his arms and legs in water - nearly five years after his accident. Doctors tell most patients that the majority of recovery occurs in the first two.
McDonald, then a neurologist at Washington University in St. Louis, devised a rigorous exercise program that electrically stimulated Reeve's muscles. Three times a week, for an hour each day, Reeve sat on a stationary bicycle with wires attached to his buttocks and legs. An electrical current set his legs in motion - as if he were pedaling on his own.
Scientists aren't sure what role the activity played in Reeve's physical gains, but they suspect it might have prompted the nerves to regrow or to form new connections.
"If you could accomplish that type of a goal in someone in a worst-case scenario, imagine what you could accomplish in the majority of cases, which are less severe," said McDonald, who will run a spinal cord regeneration center at the Kennedy Krieger Institute in Baltimore.
Several lines of research have advanced since Reeve's accident. One involves "anti-Nogo" drugs. These target the so-called Nogo protein, which researchers have found prevents growth in the nerve cell shafts, or axons, in the spinal column.
Another involves the transplantation of Schwann cells, which surround nerve cells elsewhere in the body. They have been extracted, grown and re-implanted - with some success - in gaps in the injured spinal cord. Researchers hope they will support the regrowth of spinal nerves themselves.
Also promising, according to UVA's Jane, is Chinese research into OEGs, or "olfactory ensheathing glial" cells. OEGs are nasal nerve cells involved with registering odors, but they have the ability to regenerate throughout life. Experiments in Spain have shown that rats with severed spinal cords show significant improvement in mobility after glial cell transplants.
In Baltimore, Dr. Peter Gorman, director of the spinal cord injury program at Kernan Hospital, is involved in a clinical trial of a drug, HP 184, which might help improve nerve conduction and mobility. Kernan is also testing a robotically assisted treadmill called the Lokomat, which suspends patients in a parachute harness while a mechanism strapped to their legs moves their limbs as if they were walking.
Gorman offers patients what he calls "cautious hope." Even though an outright cure for spinal injuries isn't on the horizon, he said, incremental improvements are.
"If there can be just a small amount of improvement, that can mean a world of difference in the experience of a person with spinal cord injury," he said.
Dr. Rosemarie Filart, medical director of spinal cord services at Johns Hopkins' department of physical medicine and rehabilitation at Good Samaritan Hospital, said the past decade has also seen advances in the care of people with spinal cord injury.
She cited the development of prostheses for stimulating muscle movement and bladder function, along with technologies for assisting paralyzed people in having children.
Elsewhere, research has shown that weight-bearing activity can improve nerve and cardiovascular function, slow the atrophy of muscles and reverse the osteoporosis that frequently weakens the bones of paralyzed patients.