Paralysis: New hope from studying rats
It’s an old, grim axiom of neuroscience: After an injury, the nerves in your hand, arm or leg may grow back, but neurons in the brain and the spinal cord will not.
Part of the reason is a molecule called proteoglycan — a biological insulation that separates tissues. During gestation, for example, proteoglycans prevent the placenta from growing too deeply into the uterus. “The proteoglycan molecule has been known as nature’s own barrier molecule,” says Jerry Silver, a professor of neuroscience at Case Western Reserve University.
Proteoglycan strongly inhibits the growth and movement of cells, and explains why cartilage has neither nerves nor a blood supply.
In the spinal cord, proteoglycan serves to lock the nerves into position, preventing unwanted growth. Unfortunately, when the spinal cord is injured, a new burst of proteoglycan “walls off the injury site, but also blocks nerve regeneration,” says Silver.
A bacterial balm?
Now, using an enzyme made by a deadly bacterium, Silver and his colleagues have learned to restore normal breathing in rats with a damaged spinal cord. The study, published in Nature yesterday, shows that a combination of grafting and a proteoglycan-eating enzyme called chondroitinase may sidestep the proteoglycan’s growth-deadening effect – and open a path to the holy Grail of partial repair to the spinal cord.
As scientists continue trying to rebuild the spinal cord with stem cells, the new study shows an alternative route to healing.
Spinal Cord Injury by the Numbers:
People living with a spinal-cord injury:
Annual spinal cord injuries:
Average annual medical cost:
$15,000 – $30,000
$500,000 – $3 million
The technique is rooted in evolution, Silver says. “Proteoglycans are boundary molecules that have evolved over millennia. One bacterium, proteus vulgaris knows that, and has figured out how to release this enzyme to eat through our defenses.”
That ability allows the bacterium to cause deadly septic shock.
What they did
To demonstrate that grafts plus chondroitinase enzyme could restore function, Warren Alilain, the paper’s first author:
Compressed a section of nerve in the rat’s leg, killing its neurons, but not cells that feed neurons and direct their growth
Severed a part of the spinal cord that controls one side of the diaphragm
Removed the leg nerve and attached one end — along with a drop of enzyme — above the cut in the spinal cord
Waited a week as spinal-cord nerve cells grew through the graft and reached its lower end
Attached the lower end of the graft — with a drop of enzyme — to the spinal cord just above the diaphragm nerves
Waited for recovery
It’s important to realize that when the graft was first connected to the spinal cord, it no longer contained neurons. The graft serves as a tunnel lined with cells that supply growth factors and nutrients to nerves that are growing from the upper part of the spinal cord.
The wait for recovery seemed interminable, Silver admits. “Warren Alilain, my genius post-doc, had given up, he saw no substantial return of function at two months … but at 10 weeks, he ran into my office, he saw some activity coming back.”
After another two weeks, the disconnected nerves had regained at least 80 percent of their normal electrical output in 9 of the 11 animals that got grafts and enzyme.
Spinal cord: A brainy organ?
Just getting neurons to grow in the central nervous system is not enough: the nerves must connect to the motor nerves that activate the diaphragm. After all, the spinal cord contains more than ten thousand nerve cells, and neurosurgeons cannot hope to connect them individually; and instead want to coax a process of self-connection.
The coaxing worked: among about 3,000 spinal-cord neurons that grew through the graft tube, 400 to 500 linked to the neurons that used to control the diaphragm. In other words, the growing neurons seem to be “looking” for precisely those nerve cells that must be reconnected so the diaphragm can return to work. The spinal cord, Silver says, is “smart, and that’s encouraging news. I am more optimistic than I have ever been: The gain in function is really high.”
Yet despite the crying need for better treatments for spinal cord injury, at best this technique will not be available for some years.
The technique seems unlikely to restore the complicated connections needed for walking or typing, but severe paralysis would be eased just by activating a single muscle, Silver says. Bladder control is a major issue after a lower spinal injury, and many quadriplegics require a ventilator, which can fail or cause deadly infection. Learning to reactivate the diaphragm – and to breathe — could produce huge gains in quality of life.
“This is an interesting study,” says Daniel Resnick, associate professor of neurosurgery at University of Wisconsin-Madison. “It’s a fairly vigorous model, measuring the diaphragm motion is a fairly clean measure.” Not only did the grafting process restore fairly normal breathing, but when the researchers cut the nerve graft at the end of the experiment, that removed the improvement in breathing. “That’s pretty convincing evidence that you have got neurons growing through the graft.”
The repair was not a true replacement for the spinal cord, Resnick adds. “They are not regenerating across the injury itself, but are by-passing it, going directly to the muscle. It’s not a cure for a spinal cord injury, but is a means to promote focal re-enervation, but for a high spinal cord injury, if you could get them off a ventilator, that is a big deal.”
Silver says the data also suggest that the bacterial enzyme may in some cases be effective enough to avoid grafting. “I am enthusiastic about using just the enzyme, in spinal cord injury and stroke rehabilitation,” Silver says. “Given the success to date – in our lab and others — it’s simple to do and seems to carry almost no risk — it’s just putting in a shot of enzyme as a way of stimulating neural plasticity.”
– David J. Tenenbaum
- Functional regeneration of respiratory pathways after spinal cord injury, Warren J. Alilain et al, Nature, July 14, 2011. ↩
- Spinal cord injury FAQ. ↩
- NIH: spinal cord injury info. ↩
- Spinal cord injury information network. ↩
- Breathing and spinal cord injuries. ↩
- Spinal cord injury treatment. ↩
- Costs of spinal cord injuries. ↩
- FDA approval of embryonic stem cell therapy. ↩
- Stem cells fight paralysis. ↩
- Spinal cord injury news. ↩
- The brains of your spine? ↩
- Regenerating spine nerve cells. ↩