|John Bavosi / Science Photo Library|
Nervous system injuries comprise a diverse group of disorders that include spinal cord injury (SCI) and traumatic brain injury (TBI) as well as stroke and brain cancer. SCI and TBI disproportionately affect the young, primarily because of motor vehicle accidents and violence, and stroke more commonly strikes older people, but brain tumors can develop at any age, with incidence peaking in children between the ages of 3 and 12 and in adults between 55 and 65.
The common thread among these injuries is the debilitation that typically results, which is often severe and chronic. This is because the central nervous system has such limited capacity to repair itself after an injury—whether the trauma results from a blow to the head or spine, a lack of oxygen to the brain as in stroke, or the invasion of healthy brain tissue by malignant cells. As a result, much of the basic neuroscience research relevant to nervous system injuries focuses on regeneration—that is, finding ways to jump-start the innate repair mechanisms of the brain or spinal cord to achieve some level of functional recovery. In recent years, a growing proportion of this research has focused on spinal cord injury, and 2005 was no exception.
Fixing Broken Cords
To better understand the dynamics of nerve degeneration and regeneration following a spinal cord injury, Martin Kerschensteiner and colleagues at Harvard used fluorescent dyes and time-lapse imaging to track the death and regrowth of axons in a living mouse for several days post-injury. They found that axons had partially withered within 30 minutes of the injury, and within 6 to 24 hours, many of them attempted to spontaneously regenerate. This initially robust regrowth failed, however, as the axons seemed to lose their ability to navigate in the right direction.1
The sheer complexity of the challenge in healing a severed or crushed spinal cord has demanded innovative strategies to address the central problems in regeneration: first, overcoming the molecules in myelin (the insulating sheath surrounding nerve fibers) that inhibit regeneration, as well as the scar that forms after an injury and physically impedes the reconnection of axons; second, restoring lost myelin from nerve fibers that remain; and third, inducing nerve fibers to grow across and beyond the injury to reestablish nerve connections. Continuing a trend begun in 2004, spinal cord injury researchers are increasingly relying on combined approaches to address multiple parts of the repair problem.
| Layers of protection|
Myelin, which surrounds nerve fibers called axons, plays a complex role after spinal cord injury. It must be restored to axons that remain, yet it contains molecules that discourage axon regeneration. Illustration by Benjamin Reece
One promising combination, reported in the Journal of Neuroscience by an international team of researchers anchored by Damien Pearse at The Miami Project to Cure Paralysis, used an enzyme that counteracts inhibitory signals together with two types of nervous system cells to act as structural support and guide nerve fiber regrowth in the right direction.2 This three-pronged strategy achieved significant improvements in several measures of movement ability and motor coordination when tested in adult rats with completely severed spinal cords. Although preliminary, the results provide important direction for researchers developing combined treatment regimens for spinal cord injury in humans, according to the authors.
A second experimental treatment combined stem cells with gene therapy to remyelinate nerve fibers in rats with spinal cord injuries, effectively improving the animals’ ability to walk, according to work reported in the Journal of Neuroscience by Scott Whittemore and colleagues.3 The therapy teamed stem cells called glial-restricted precursor cells, which have “committed” to becoming central nervous system support cells, with gene therapy designed to mimic the effects of two types of nerve growth factors.
The combination promoted the growth of myelin and enhanced nerve signal transmission along the resheathed nerve fibers, which corresponded with improved motor function. The study provided the best demonstration to date that boosting myelin growth can lead to functional improvements, according to a statement from the National Institute of Neurological Disorders and Stroke, which funded the research.
Another study, from the biotech firm Biogen Idec, combined an “old” drug with known anti-inflammatory action, methylprednisolone, with an experimental “Nogo blocker,” a drug that is being investigated for its ability to block inhibitory signals that restrict nerve growth (via a receptor called Nogo-66).4 Tested in rats with spinal cord injury, the combination had a more pronounced effect on recovery of movement and coordination and on axonal growth than either treatment alone, suggesting that each may work through different mechanisms.
Apart from trying to manipulate molecules that restrict or guide axons on their journey to regrow after an injury, deciphering these molecules continues to be a central emphasis of basic spinal cord research. Much of this work has focused on one or more of the three known myelin-based inhibitors, known as Nogo, MAG, and OMG, as scientists work on elucidating the molecular structures that underlie nerve growth inhibition. Several groups have reported separate findings that are gradually revealing the intricacies of how this cellular machinery works.
Separate teams of Nogo researchers have observed contradictory effects of blocking or deleting the Nogo receptor in laboratory animals. A multisite team anchored by Marc Tessier-Lavigne, a Howard Hughes Medical Institute neuroscientist now at Genentech, reported in Proceedings of the National Academy of Sciences that genetically deleting the Nogo receptor from laboratory animals or cultured cells did not free nerves to regrow.5 Although this study contradicted other findings suggesting that Nogo is responsible for inhibition, it underscored that the receptor is probably not the simple on/off mechanism its name suggests.
In fact, Steven Strittmatter’s group at Yale showed just how complex the Nogo receptor is. They reported in a Journal of Neuroscience article that different molecular pathways through the receptor exert different effects.6
Other clues in the Nogo molecular puzzle came from independent teams from Children’s Hospital Boston and from Biogen Idec. Reporting separately in Neuron, the teams discovered that a protein variously called TAJ or TROY is an important part of the Nogo receptor complex.7,8 Hunter College’s Mary Filbin and colleagues published a study, also in Neuron, in which they identified a pathway in the Nogo receptor that may be where the three known myelin-based inhibitors of axonal regeneration interact.9
New work suggests a fourth major player in nerve growth inhibition.
New work suggests a fourth major player in nerve growth inhibition (in addition to Nogo, MAG, and OMG). A University of Texas–Southwestern team led by Luis Parada reported in Proceedings of the National Academy of Sciences that a molecule known to play a role in guiding axon development in fetuses, ephrin-B3, remains active through life to inhibit nerve fiber outgrowth in myelin and that its inhibitory activity is equivalent to that of the other three families of inhibitors combined.10
Harnessing Stem Cells for the Spine
Slowly but surely, scientists are making progress in learning how best to harness stem cells, in all their variations, for the goal of spinal cord repair. In 2005, a number of researchers inched toward this goal, including two separate groups at the University of California at Irvine.
Hans Keirstead and colleagues restored myelin in rats with spinal cord injuries and improved their capacity to move around by transplanting glial support cells called oligodendrocytes, which they had successfully developed from human embryonic stem cells grown in culture dishes.11 In research reported in the Journal of Neuroscience, the team saw benefits when the cells were transplanted seven days after the injury, but not when the transplant took place 10 months after the surgery, suggesting an early therapeutic window of opportunity.
The second study, reported in Proceedings of the National Academy of Sciences by Brian Cummings and colleagues, used adult neural stem cells from humans to regenerate myelin and improve mobility in mice with spinal cord injuries.12 When the cells were transplanted nine days after an injury, they developed into oligodendrocytes that restored the insulating myelin sheath around nerve fibers, and the mice showed improved mobility.
Long-awaited results from the large government-funded Women’s Health Study found that vitamin E does not protect women from stroke (or heart attack or cancer). The data, published in the Journal of the American Medical Association, add important new information to the ongoing debate about the health benefits of vitamin E supplementation, finding no support for recommending the antioxidant as preventative therapy for cardiovascular disease or cancer.13
On the diagnostic side, researchers from Johann Wolfgang Goethe University in Frankfurt, Germany, found that strokes affecting the right side of the brain are not recognized as frequently as those that strike the left side of the brain.14 Reporting in the Lancet, the team hypothesized that the more subtle symptoms characteristic of right-hemispheric strokes make them more difficult to identify, thus making an effective response a challenge.
The final report of the Glioma Outcomes Project, which studied patterns of care for adults with newly diagnosed gliomas, or glial cell tumors, found that doctors treating patients with these malignant brain tumors are not following published guidelines in a few key areas, including chemotherapy, which is apparently being underused.15 Of particular concern was the finding that 80 percent of patients with cancerous brain growths received anti-epileptic drugs to prevent seizures, for which people with brain tumors are at increased risk. However, these drugs seem to have little value for patients with no history of seizures, and they carry significant side effects. The study, published in the Journal of the American Medical Association, provides benchmark data that will enable clinicians to better plan and assess treatment, the authors wrote.
Researchers at the University of Alabama at Birmingham reported in the Journal of Neuroscience that a drug currently used to treat inflammatory disease can switch off a protective molecular defense mechanism used by gliomas. In preliminary animal studies, the drug, sulfasalazine, which is FDA-approved for inflammatory bowel disease and rheumatoid arthritis, dramatically reduced tumor size when administered by injection into a membrane that lines the walls of the abdomen.16 Meanwhile, a study in rats by Gail Clinton and colleagues at Oregon Health and Science University showed that herstatin, a protein that inhibits enzymes involved in tumor cell proliferation, blocks the growth of glioblastoma, a type of glioma that is particularly aggressive and deadly. The findings, published in Clinical Cancer Research, suggest an avenue of potential therapy for another type of tumor that affects glial cells.17
Steroids and Traumatic Brain Injury
Despite a 30-year history of use in traumatic brain injury, a group of powerful anti-inflammatory drugs called corticosteroids do not help head injuries, according to results published in the Lancet of a trial involving 10,000 adults with head injury.18 The authors reported that using these drugs following an acute injury actually increases the risk of death within two weeks and makes it more likely that the patient will die or be severely disabled within six months of treatment. In a statement released by the journal, lead author Phil Edwards of the London School of Hygiene and Tropical Medicine called for an urgent re-evaluation of the practice of treating head injuries with corticosteroids.
Neural Prosthetics for Post-Injury Recovery
Hundreds of thousands of Americans are paralyzed or have severely limited mobility from injuries or diseases of the nervous system. For many of them, so-called neural prosthetics may represent the only hope for regaining a measure of independence. The idea is to capture nerve signals with electrodes implanted in the brain and translate the signals into movements on a prosthetic limb or a computer mouse, thereby enabling the person to use thought power alone to achieve a task such as grasping food or activating a computer-controlled light switch. A handful of specialized laboratories continue to advance the development of such “brain-machine interfaces.”
Researcher Miguel Nicolelis poses with a monkey involved in research in which monkeys treated a robotic arm as their own—revealed by structural changes in their brains— after they learned to control it with their brain signals. Photograph by Les Todd
Miguel Nicolelis and his team at Duke University found that monkeys trained to use their brain signals to control a robotic arm are undergoing structural brain changes that treat the arm as if it were their own appendage. The research, published in the Journal of Neuroscience, has implications for restoring function in paraplegics and others debilitated by neurological disorders.19 Meanwhile, Andrew Schwartz’s team at the University of Pittsburgh reported at the annual meeting of the American Association for the Advancement of Science that a monkey outfitted with a robotic prosthesis the size of a child’s arm learned to directly control the arm well enough to feed itself chunks of fruits and vegetables.20