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PROGRESS IN SPINAL CORD RESEARCH
FROM HOPELESSNESS TO CAUTIOUS OPTIMISM

Neurologists know better than anyone that people with spinal cord injuries hunger for any news of breaking research, giving hope that spinal cord function can be restored. When news stories are published with startling headlines about miraculous surgeries, neurologists get calls from patients who want to know, “Can this be done for me?”

As with medical research in general, the breakthroughs in spinal cord research have been incremental rather than dramatic. Animal studies of inhibitory molecules today may lead to partial recovery – in terms of patients getting off mechanical ventilation, for example – but they do not necessarily promote complete recovery that includes walking. However, these studies have shifted the perspective on spinal cord research from pessimism to cautious optimism. In separate telephone interviews, experts in spinal cord research discussed their own work and the direction that the field is going.

“We are writing the books on what can be done to enhance regeneration after spinal cord injury,” said W. Dalton Dietrich, PhD. “The focus is on changing the environment in the spinal cord so that it's more permissive, so we can wake up the neurons and get them to grow.” Dr. Dietrich is the Scientific Director of The Miami Project to Cure Paralysis, and the Kinetic Concepts Distinguished Chair in Neurosurgery at the University of Miami in Florida, where he is Professor of Neurological Surgery, Neurology, and Cell Biology and Anatomy.

“There are multiple parts of the puzzle,” he said. “We will not discover just one magic bullet that will cure paralysis. Instead, there are a variety of small steps and stages that have to be targeted with different types of therapies. We need to get the axons not only to regenerate, but also to myelinate in order to function.”

INFLAMMATORY RESPONSE

The inflammatory response is an example of the challenge posed by targeting issues related to spinal cord injury, Dr. Dietrich said, noting that this is an area of focus in spinal cord injury research (Curr Opin Neurol 2002;15(3):355–360).

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Dr. W. Dalton Dietrich: “We are writing the books on what can be done to enhance regeneration after spinal cord injury.”

“In a spinal cord injury, the early inflammatory response may contribute to overall damage,” he said. “We're trying to develop new drugs and strategies to limit the acute injury response, such as hypothermia, and medications, such as certain corticosteroids and the new anti-inflammatory cytokines that target the inflammatory cascade.

“However, targeting inflammation is a double-edged sword,” he continued, “because inflammation in the chronic state is reparative. It clears out tissue, allows new cells to come in, and promotes recovery and function. So some strategies may be bad at one time, good at another.”

STEM CELL TRANSPLANTATION

Another area of focus in animal studies is stem cell research. Hideyuki Okano, MD, PhD, and colleagues recently published their findings regarding stem cells from a single rat fetus that can be used to treat spinal cord injuries in several adult rats (J Neurosci Res 2002;69:925–933). He is Professor and Chair of Physiology at Keio University School of Medicine in Tokyo, Japan.

In this study, Dr. Okano and his team of researchers transplanted neural stem cells developed in vitro into injured spinal cord tissue in adult rats. The cells produced new neurons, which in turn formed synaptic structures in the host tissue. The treated rats also showed significant motor improvement that was not seen in the control rats.

“It was important that the stem cell transplantation take place nine days after injury,” he said. “If we transplant earlier, the donor cells do not survive well. Alternatively, even the survived cells preferentially differentiated into astroglia, but not to neurons. We believe that these effects result from inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1b, and interleukin-6, which are released from the immune cells at the inflammatory stage.

“Nine days after the injury, the inflammatory stage is over and the presumed change in the microenvironment may induce the generation of new neurons from the transplanted neural stem cells.”

Five weeks after the transplantation, he and colleagues tested the rats on a skilled-forelimb reaching task. “Rats that had the stem cell transplants performed better than controls,” he said. “The improvement seemed to result from the transplant's ability to form new neurons that integrate into the neuronal circuits. The new neurons generated from transplanted stem cells formed connections or synapses with other neurons, including the motor neurons, which control voluntary movement.”

Evidence of neuronal regeneration was confirmed by histology and analysis of the rats' motor behavior, the investigators reported. A skilled teaching task showed functional recovery, they said.

SCAR OR REMYELINATION?

One of the questions facing spinal cord regeneration researchers is whether the focus should be on the glial scar, the lesion that forms after a spinal cord injury, or on the myelin, according to Jerry Silver, PhD. “Since the mid-1980s, I've been interested in why the nerve fibers grow where they do, as well as the places where axons don't grow normally,” said Dr. Silver, Professor of Neuroscience at Case Western Reserve University in Cleveland, OH.

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Dr. Jerry Silver said one of the questions facing spinal cord regeneration researchers is whether the focus of inquiry should be on the glial scar, the lesion that forms after a spinal cord injury, or on the myelin.

Dr. Silver has focused on molecules that inhibit neuronal growth. The regions hostile to neuronal growth, the boundary regions of the brain and nervous system, contain extracellular spaces that are filled with proteoglycans, a type of inhibitory molecule. He and colleagues found that proteoglycans were also present in the glial scar.

They also found that if neuronal cells were placed gently enough into the white matter of the rat forebrain, they could avoid producing an injury that broke the blood-brain barrier, and thus set in motion the inflammatory response that creates the glial scar (Nature 1997;390:680–3). Although white matter is typically hostile to neuronal growth, the implanted cells could regenerate, he said. Subsequent research on the mouse spinal column showed again that, if the inflammatory response was avoided, cells could regenerate.

In ongoing research, he and colleagues are seeking to identify a way to target enzymes such as xylotransferase-1, which facilitate the assembling of proteoglycans. In other words, if researchers can inhibit the inhibitor molecule, can they also free up neuronal regeneration? “There is incredibly robust potential for the regeneration of sensory neurons beyond the glial scar, and the potential remains for long periods of time,” said Dr. Silver, noting that patients with spinal cord injuries report that the lack of sensation is as devastating as paralysis. “It's clear that proteoglycans are a critical part of the inhibitory mechanism in the region of the glial scar. We have to get rid of the inhibitor, and we have reagents that are being developed to accomplish that goal.”

STIMULATING REGROWTH

“The failure of central neurons to regenerate is a series of different problems,” said Clifford Woolf, PhD. “One is the issue of the death of some neurons when they're injured, and increasingly, we're beginning to understand why they die – we're looking at ways to prevent that.” Dr. Woolf is the Richard J. Kitz Professor of Anesthesia Research at Massachusetts General Hospital and Harvard Medical School in Cambridge.

“Next we need to know what prevents them from regrowing. The adult central nervous system is hostile to growth, partly due to the glial scar, and partly due to the myelinated fibrotracts,” Dr. Woolf explained.

The myelin in the central nervous system is produced by glial cells, known as oliodendrocytes, which make proteins that inhibit growth, he wrote in a recent Science article (2002;297(5584):1132–1134). These growth-inhibiting proteins go on to become embedded in the myelin sheath.

Figure

Three growth-inhibitory molecules – MAG (red), OMgp (orange), and the extracellular Nogo-66 domain of Nogo-A (yellow) – are produced by oligodendrocytes in the central nervous system. These growth-inhibitory proteins become embedded in the myelin sheath that surrounds axons, and they block the regeneration of the nerve fibers. They all bind to the same neuronal receptor NgR (pink), resulting in the activation of signaling pathways that block axonal growth and induce growth cone collapse. The photomicrographs depict primary adult dorsal root ganglion neurons grown either in a laminin substrate that is permissive for growth (right) or on a CNS myelin substrate that prevents growth (left).Reprinted with permission from Science 2002;297(5584):1133. Copyright 2002 American Association for the Advancement of Science.

He and fellow researchers are particularly interested in exploring the function of inhibitory molecules and the receptors with which they interact. They have described the interaction of these inhibitory molecules and their receptors. In earlier research, they noted that investigators have identified three inhibitory molecules: Nogo-A, so named for its inhibitory affect, myelin-associated glycoprotein (MAP), and oligodendrocyte myelin glycoprotein (OMgp), and determined that they all bind to the same receptor, NgR (Science 2002; 297:1190–1197).

“We need all three,” he said. “Our work has centered on comparing the neurons in development and the gene expression patterns of those that grow with those that don't grow. We're beginning to analyze the presence or absence of genes required for the growth of axons. Next we'll be trying to get injured central neurons to produce these genes, and perhaps use viruses as vectors.”

He agreed with other experts that the future looks bright for spinal cord research. “Ten years ago, we did not envision the possibility of clinically significant repair. While it will be incredibly difficult, it is no longer the realm of science fiction. As we are defining the different elements, we may eventually have a combination of interventions to allow regrowth to restore some function.”

NEUROPROSTHETIC DEVICES

Other recent animal research shows that monkeys with impaired motor control can be trained to move computer screen cursors with the aid of so-called “neuroprosthetic devices” (Nature 2002;416:141–2). “In the future, technology like this will be an option for paralyzed individuals,” said principal investigator John P. Donoghue, PhD, Professor of Neuroscience at Brown University in Providence, RI, where he directs a laboratory.

“The device bypasses the injury and allows the individual to communicate, for example, by means of any technology, like a computer, that has a ‘point-and-click’ function.”

In the study, Dr. Donoghue and the team of researchers recorded the activity of motor cortex neurons in three Macaca mulatta monkeys, which had received implants of the neuroprosthetic devices. Dr. Donoghue and his colleagues found that one of the monkeys used neural control rather than hand control to move the feedback cursor to different targets, and used neural activity-based signals to carry out the task without further training.

“In another generation, we may see a free-hand system that sends signals to the paralyzed muscles,” said Dr. Donoghue. “We're looking at devices that interface with the brain, ideally to restore as much function as we can.”

FOR MORE READING ON SPINAL CORD RESEARCH

  • Davies SJ, Goucher DR, Doller C, Silver J. Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J of Neurosci 1999;19:5810–5822.
  • Liu BP, Fournier A, GrandPre T, Strittmatter SM. Myelin-associated glycoprotein as a functional ligand for the nogo-66 receptor. Science 2002;297(5584):1190–1197.
  • Ogawa Y, Sawamato K, Miyata T, Miyao S, et al. Transplantation of in vitro-expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats. J Neurosci Res 2002;69:925–933.
  • Serruya MD, Hatsopolous NG, Paninski L, Fellows MR, Donoghue, JP. Brain-machine interface: Instant neural control of a movement signal. Nature 2002;416:141–142.
  • Woolf CJ, Bloechlinger S. It takes more than two to nogo. Science 2002;297(5584):1132–1134.