A gift from United Spinal to the Center for Neuroscience and Regeneration Research provides the opportunity for a prognosis for SCI research-and the outlook is positive!
By Rob Ingraham
“Some of you remember 20 years ago, even 10 years ago, I couldn’t honestly use the word ‘cure’ in the context of spinal cord dysfunction. We weren’t there. Today we can use this word. It is an achievable goal; it’s an objective that we can get to. It’s going to take a lot of work, but a cure is an achievable objective. There’s been absolute revolution in spinal cord research and your center has been at the forefront.”
This is how Dr. Stephen G. Waxman characterized progress at one of United Spinal Association’s most successful collaborations—The Center for Neuroscience and Regeneration Research at the West Haven Connecticut VAMC. At its annual open house for United Spinal board members and staffers in December 2005, Dr. Waxman, director of the Center, accepted a check for $100,000 from the Association to support ongoing research and summarized the Center’s history and its numerous “firsts” in understanding the mechanisms behind spinal cord dysfunction. To date, United Spinal has contributed nearly $8 million in research grants to the West Haven facility.
The Center, founded in 1986, is a collaboration of United Spinal, Yale University School of Medicine, Paralyzed Veterans of America, and the Department of Veterans Affairs. It currently has a staff of more than 35 scientists and support personnel and hosts visiting researchers from around the world, including Great Britain, Germany, Italy, Israel, Japan, and China.
“Our mission is to restore function after spinal cord and brain injury,” Waxman said. “And we’re different from the usual academic department, where academic freedom is paramount. We trade in our academic freedom for the power of a multi-disciplinary route-cell biologists, molecular biologists, proteomic specialists, informatics specialists, neurophysiologists, pain physiologists, primate scientists, all working together.”
The “firsts” that the Center for Neuroscience and Regeneration Research can claim include:
• The first demonstration of the molecular basis for remission in multiple sclerosis (MS). “MS is unique among diseases of the spinal cord in that individuals can lose the ability to walk, they can lose the ability to see, lose coordination, and then regain it,” Waxman said. “It was this Center that worked out the molecular basis. We can’t yet induce remissions, but that’s on the drawing board. It’s turned from an impossibility to a reachable objective.”
• The first demonstration of a population of nerve fibers that maintains continuity but fails to function due to loss of myelin in spinal cord injury (SCI). In some types of SCIs, the spinal cord axons are spared but some of these axons lose their myelin sheath due to the injury-induced death of myelin-producing cells. This idea has led to a paradigm shift in current research and opened up the possibility of restoring function via the remyelination of the demyelinated spinal cord axons.
• First molecular dissection of nerve fibers within the normal and injured spinal cord. The Center performed the first dissection of the molecular architecture of myelinated nerve fibers. The work demonstrated that “sodium channels” are not continuously distributed along myelinated nerve fibers, but are clustered in large numbers in certain regions. This was important because it showed that, in demyelinated axons, the bared axon membrane lacks the machinery to generate nerve impulses.
“Why be interested in sodium channels?” Waxman asked. “Within our spinal cords, where sensory information ascends and motor information descends, many of the axons are myelinated and they depend on these molecules, these sodium channels, which act as ‘molecular batteries’ carrying information along the axons. It’s the sodium channels that make nerve cells special and allows them to conduct impulses. The myelinated nerve fiber is a beautiful piece of architecture with the sodium channels just where you need them; it’s very elegant and economical except that when that myelin is injured, the membrane of the nerve fiber exposed doesn’t contain sodium channels. So it’s not just loss of insulation; it’s that the opening is exposing membrane with ‘nobody home.’ And yet we know that in MS, remissions occur even though there is very little remyelination. And we now know that what happens- from work that came out of this building-is that this membrane that doesn’t contain sodium channels reorganizes and acquires them and acquires the capability to conduct impulses; a beautiful, beautiful example of adaptive plasticities. So we now know what happens, we want to be able to control that process and induce it.”
• First identification of molecules that trigger degeneration of spinal cord axons. “How do axons die after they’re bruised?” Waxman continued. “That’s been an unknown area. The majority of neuroscientists are interested in the brain; that’s where thinking occurs, everyone wants to understand memory and things of that sort. We’ve been interested, though, in neurofibers in the spinal cord. How do they die after they’re initially bruised? And we’ve worked out, for the first time ever, that molecular cascade, which opens up the possibilities of protective strategies that will protect injured axons, so they don’t pack up and die.”
• First demonstration of the molecular basis for pain after SCI.
• First use of novel methods to reduce pain after injury to the spinal cord. “Neuropathic pain occurs after traumatic amputation and we all know that it occurs after spinal cord injury,” Waxman explained. “In my view, neuropathic pain represents a very significant unmet medical need [and] it’s an area in which there will be rapid progress—again, a lot of it coming out of this Center. We know precisely the molecules that are generating the pain response. This has ignited an avalanche of interest in the pharmaceutical industry. Since we’ve published this, last year at the Neuroscience meeting there were over a dozen papers from the pharmaceutical industry looking for blockers for this particular channel, and there’s no question in my mind there will be new classes of drugs and more effective medications for neuropathic pain in the foreseeable future.”
• First demonstration that cell transplantation can enhance nerve impulse conduction in the injured spinal cord. United Spinal staff and Board members pose with the Center’s researchers on a day the two organizations rededicated their mutual commitment to finding a cure for spinal cord dysfunction.
The Center conducted a pivotal study on restoring function in the injured adult rat spinal cord, demonstrating that myelin-forming cells can be transplanted to the central nervous system where they survive, produce new myelin, and restore normal conduction along axons within the spinal cord. This discovery has led to studies now in progress at numerous laboratories employing a variety of myelin- forming cells and modes of cell delivery.
• First demonstration that bone marrow stem cells-introduced intravenously-can protect the injured brain and spinal cord. In an effort to determine the optimal cell types for transplantation, Center scientists were the first to demonstrate the remyelinating potential of intravenously-administered bone marrow cells, providing proof of principle for an attractive therapeutic approach that is both minimally invasive and easy to adopt.
• First human study on transplantation of myelin-forming cells into the injured nervous system. The Center was the first to develop and characterize the methodology for preparation of Schwann cells-a type of cell found in the myelin sheath, which surrounds nerve cells and holds them in place while also insulating nerve cells from each other-for transplantation into the brain and spinal cord of people with MS, and investigate its potential in a first-in-human study of myelin repair. This Phase 1 study demonstrated the safety of the transplantation procedure and has provided the infrastructure for future clinical studies in people with MS.
“Your Research Matters”
Describing the first few visits by United Spinal members to the Center, Waxman noted, “Imagine the—to me—beauty, of nerdy biophysicists sitting in front of their computers and oscilloscopes trying to explain an ‘inward rectifier’ to somebody that’s not a scientist, in a wheelchair, and that person is saying to the scientist, ‘Number one: Can you say that in English? Because I want to understand it.’ And there’s an important lesson there because we serve society, we’re not doing poetry. And the second message from that visitor was: ‘Stay with it. Those experiments matter because the spasticity that you talk about is not an abstraction-I’ve got it. We’re counting on you, and your research matters.’”
“We are moving closer, month by month, to victory in our battle against spinal cord dysfunction,” Waxman maintains. “We will win this battle. And when we do, United Spinal Association will be at our side.”
