Paralyzed rats relearn to pee 
 
 Bladder control restored for the first time in animals with stark spinal cord damage 
 
 By Meghan Rosen 
 
 Bladder control restored for the first time in animals with stark spinal cord damage 
 
 By Meghan Rosen 
 
 Web edition: June 25, 2013 
 
 Print edition: August 10, 2013; Vol.184 #3 (p. 11) 
 
 Paralyzed rats can now decide for themselves when it’s time to take a leak. Animals in a new study regained bladder control thanks to a new treatment that coaxes severed nerves to grow. 
 
 Instead of dribbling out urine, the rodents squeezed out shots of pee almost as well as healthy rats do, researchers report June 25 in the Journal of Neuroscience. The study is the first to regenerate nerves that restore bladder function in animals with severely injured spinal cords. 
 
 “This is a very big deal,” says neurologist John McDonald of the Kennedy Krieger Institute in Baltimore, Md. If the treatment works in people with spinal cord injuries, he says, “it would change their lives.” 
 
 Unlike paralyzed rats, severely paralyzed humans can’t leak urine to relieve a full bladder. Unless injured people are fitted with a catheter, urine backs up into the kidneys. “These people get kidney failure all the time,” says study leader Jerry Silver, a neuroscientist at Case Western Reserve University in Cleveland. “It’s a terrible problem. If they didn’t have the catheter, they would die.” 
 
 Some of the worst spinal cord injuries sever the bundle of nerve cells that reach from a mammal’s brain down through the vertebrae. The neurons can’t just grow back. Instead, the cells’ stumps get stuck in a gummy thicket of scar tissue that forms around the wound. 
 
 Silver’s team has spent years refining a technique to tear down scar tissue and encourage damaged nerve cells to grow. The researchers snip out a healthy nerve bundle from between rats’ ribs, graft it onto a damaged section of spinal cord and then add an enzyme that chews up scar tissue. In 2006, his team used the technique to return some limb control to rats with one paralyzed forepaw. And in 2011, they helped paralyzed rats regain the ability to breathe. 
 
 In both cases, the rats retained bladder control after their injury because researchers had snipped only halfway through the bundle of spinal cord nerves. For the new study, the researchers chopped out a hunk of the rats’ spinal cords, severing the entire nerve bundle and leaving a gap about the width of a pencil. They then pumped up the treatment protocol from the earlier studies by adding a growth factor to the injury site. 
 
 Over several months, the damaged nerves slowly regenerated. They inched down through the grafted nerves, and then, says Silver, “they kept going and going like little Energizer bunnies.” After six months, the rats could mostly control their bladders and could even wiggle their legs a bit. 
 
 The new method may have potential beyond restoring bladder control. It could also restore sensation to the skin, which could help paralyzed people detect and avoid bedsores, says neuroscientist Lars Olson of the Karolinska Institute in Stockholm. “This is one of the most important steps that I have seen in recent years,” he says. ||||| Image caption Nerve regeneration in the rat 
 
 US scientists say they have made progress in repairing spinal cord injuries in paralysed rats. 
 
 Rats regained some bladder control after surgery to transplant nerve cells into the spinal cord, combined with injections of a cocktail of chemicals. 
 
 The study, published in the Journal of Neuroscience, could raise hopes for one day treating paralysed patients. 
 
 But UK experts say it will take several years of research before human clinical trials can be considered. 
 
 Scientists have tried for decades to use transplants of nerve cells to restore function in paralysed animals by bridging the gap in the broken spinal cord. 
 
 However, coaxing the cells to grow and form new connections has proved elusive. 
 
 One problem is the growth of scar tissue as the body's responds to injury, which seems to block cell regeneration. 
 
 If we can show in a larger animal that our technique works and does no additional harm I see no reason why we couldn't move rapidly in humans Dr Jerry Silver, Case Western Reserve Medical School, Cleveland, Ohio 
 
 US scientists carried out complex surgery to transplant nerves from the rodents' ribs into the gap in the middle of their spinal cord. 
 
 They also used a special "glue" that boosts cell growth together with a chemical that breaks down scar tissue in an attempt to encourage the nerve cells to regenerate and connect up. 
 
 The researchers found for the first time that injured nerve cells could re-grow for "remarkably long distances" (about 2cm). 
 
 They said that while the rats did not regain the ability to walk, they did recover some bladder function. 
 
 Lead author Dr Jerry Silver of Case Western Reserve Medical School, Cleveland, Ohio, said: "Although animals did not regain the ability to walk, they did recover a remarkable measure of urinary control." 
 
 Co-author Dr Yu-Shang Lee of the Cleveland Clinic, Ohio, added: "This is the first time that significant bladder function has been restored via nerve regeneration after a devastating cord injury." 
 
 The findings may help future efforts to restore other functions lost after spinal cord injury. 
 
 They also raise hope that similar strategies could one day be used to restore bladder function in people with severe spinal cord injuries. 
 
 Dr Silver said further animal experiments will be needed to see if the technique could work in humans. 
 
 He told BBC News: "If we can show in a larger animal that our technique works and does no additional harm I see no reason why we couldn't move rapidly in humans." 
 
 'Remarkable advance' 
 
 Commenting on the study, Dr Elizabeth Bradbury of King's College London said several challenges must be overcome before the therapy can be trialled in patients. 
 
 "There are a number of challenges before this therapy can be brought to the clinic," she said. 
 
 "Nevertheless this is a remarkable advance which offers great hope for the future of restoring bladder function to spinal injured patients and if these challenges can be met we could be reaching clinical trials within three to five years." 
 
 Dr John Williams, head of neuroscience and mental health at the Wellcome Trust, said the implications for people are not yet clear. 
 
 "This is one of a number of ways that one can approach restoration of bladder function in paralysed patients, but careful studies will be needed to optimise which of the technologies under investigation might be of most benefit to patients." ||||| Shutterstock 
 
 A team of neuroscientists has grafted nerves onto the severed spinal cords of rats, enabling the rodents to regain bladder control. 
 
 Though human trials are a way away -- the team wants to trial the method on larger animals first -- the news is an astonishing breakthrough for the field. Surveys have shown that bladder control, along with bowel control, ranks as one of the highest priorities for recovery of the spinal cord injury community where the spine is totally severed (aside from, obviously, regaining control of limbs). It not only makes everyday life more difficult, but loss of bladder control can lead to serious infections as catheters are used to provide individuals with more independence. Methods of alleviating discomfort or risk of infection generally involve surgery, for instance enlarging the bladder by using a portion of the intestine, thus ensuring a catheter can be used less frequently. 
 
 Many attempts have been made in the past to graft nerve cells from another part of the body onto the spinal cord to promote regrowth and connections. The idea is if we can engender the right conditions, axons (nerve fibres) will begin to grow out from the nerve cells and eventually reach connections on the spine below the line of paralysis, returning the brain's capacity to communicate with muscles below that line. Axons are responsible for carrying electrical impulses, so if they can safely regenerate at the base of the spine they could act as a bridge connecting healthy nerves either side of the break. 
 
 The problem has been the scar tissue around the original wound, which tends to be extensive, and the scar tissue that will inevitably form from yet another surgery at the site of the graft. In the past attempts have been made to physically cut away the scar tissue so that axons have the room and capacity to penetrate the site and bridge the gap. 
 
 Focusing on this barrier, the team of neuroscientists from Case Western Reserve and Cleveland Clinic decided to try using an enzyme to minimise scar tissue, while introducing a growth factor to encourage cell growth and axon recovery in the graft. 
 
 Peripheral nerves were first transplanted to the site of the break. Schwann cells, which are integral to peripheral nerve biology and wrap around axons, reside in the remaining nerves and act to encourage and support axon regrowth. To get the axons to grow enough to bridge the gap and travel 2cm down to integrate into the nerve cells on the other side of the chasm, the team introduced fibroblast growth factor, heparin-binding proteins often used to encourage wound healing. This helped prompt the Schwann cells into action. Then the enzyme chondroitinase was introduced, which had already been identified in 2008 as a tool for digesting scar tissue molecules while at the same time encouraging nerve plasticity. It's an enzyme that has proven to be most efficiently administered via viral vectors by a Cambridge University-Kings College London team, a method that saw more scar tissue molecule removal round the spinal cord injury site than ever before. 
 
 It was a slow recovery, but six months later the rats were once again able to urinate without assistance. 
 
 "While urinary control is complex and recovery took several months, it was clear that this primitive function lost to spinal cord injury does possess the capacity to rewire itself, even when a relatively small number of axons are regenerated," Jerry Silver, a professor of neurosciences at the Case Western Reserve School of Medicine, said in a statement. "We were especially surprised and excited to discover that once a permissive environment was created, a subset of neurons situated largely within the brainstem, which play important roles in bladder function, slowly re-grew lengthy axons far down the cord." 
 
 Once larger animal trials have been carried out, the team is hopeful it will move on to human trials, but this will be some years away. Elizabeth Bradbury of Kings College London -- involved in the aforementioned chondroitinase trial run with Cambridge University -- told the BBC this could be "within three to five years", if the necessary barriers are overcome. 
 
 The rats did not regain any ability to walk, nor did they regain full bladder control. However the amount they did regain is considered significant.
– Neuroscientists working with rats have pulled off a feat raising hopes that paralyzed people might someday be able to regain control of their bladders and ditch the catheter. The scientists grafted nerves from elsewhere in the rats' bodies to their severed spinal cords, and the rats eventually were able to pee again almost as well as healthy rats, reports Science News. The rats were not able to walk again, and while they didn't regain full control of their bladders, the study is still "an astonishing breakthrough for the field," writes Liat Clark at Wired. Any similar research on humans is still years away because the results must first be replicated on animals bigger than rats, reports the BBC. Previous attempts to regenerate nerves on damaged spinal cords were stymied by scar tissue at the site of the original injury. The scientists were able to overcome that by using an enzyme to break down the scar tissue, in tandem with a growth factor that helped the transplanted nerves grow. "This is one of the most important steps that I have seen in recent years,” says an Oslo neuroscientist not involved with the study.