When actor Christopher Reeve injured his spinal cord in a horse-riding accident, people all over the world realized that the star of "Superman" movies had become a different kind of hero. Today, Reeve is a strong advocate for more research on spinal cord injury.

Until recently, many scientists believed that damage to nerve cells in the central nervous system (the brain and spinal cord) could not be repaired. But within the past few years that attitude has begun to change; experiments with laboratory animals are revealing that some regeneration and recovery might be possible.

The articles in this series offer a glimpse of the kinds of research that increase our understanding about nervous system development and function. They also show how scientists use that fundamental information to help improve treatments for people who have spinal cord injuries.

Research Overview: Studies Of Spinal Cord Injury Trigger More Questions

On Memorial Day weekend in 1995, in a devastating accident, an experienced rider was thrown head first from his horse during a jumping competition in Culpeper County, Virginia. He fractured the first two vertebrae in his neck and crushed his spinal cord just as it exits from the skull.

The 42-year-old man received emergency resuscitation, which saved his life, but he lost sensation in most of his body and the ability to move his arms, legs, and torso. The rider, of course, was actor Christopher Reeve, who has since become a prominent advocate for more research on spinal cord regeneration.


People magazine cover highlighting Christopher Reeve's tragic accident

When Reeve was injured, he received state-of-the art medical care, including methylprednisolone. Scientists had studied this steroid drug for years before they learned that it can sometimes prevent complications associated with spinal cord injury if given immediately after the trauma occurs. Although the damage to Reeve's spinal cord was severe, he has regained some of the function of his spinal nerves just below the site of injury. He and thousands of other people with spinal cord injuries now await new treatments that will at least lessen the severity of their paralysis.

Today, much of the excitement -- and many of the questions -- about repairing damaged tissue in the brain or spinal cord focuses on coaxing injured nerve cells to regenerate and recover their lost functions. Some researchers believe it may be necessary to replace entire nerve cells that have died, after the brain is damaged by head trauma or by degenerative diseases such as Parkinson's. But in spinal cord injuries, nerve cell bodies usually survive. So researchers seek ways to regrow damaged axons, the thin fibers that extend from nerve cell bodies and signal the next nerve cell to respond.


The central nervous system (CNS - yellow) includes the brain and spinal cord, both of which are protected by bone. The peripheral nervous system (PNS - purple) lies outside the CNS and supplies the muscles, tissues, and organs of the body.

Triggering spinal cord axons to regrow is not a simple matter, however. The axons travel in bundles or pathways up and down the cord, and each pathway carries different kinds of information. The downward or descending pathways from the brain to the spinal cord control a person's deliberate or voluntary movements. The upward or ascending pathways from the spinal cord to the brain carry sensory information about touch, pain, temperature, and body position. Thus, spinal cord injuries that damage both the descending and ascending pathways affect a person's ability to move and to feel sensation.

But even if researchers can stimulate injured spinal cord axons to regrow up and down the spinal cord, the problem may not be fixed. "Axons need to do more than grow," says Wise Young, a neurologist and research scientist in the department of neurosurgery at New York University Medical Center in New York City. "They also need to attach to their target cells." The point at which the endings of a nerve cell axon contact the next cell is not a physical attachment, however. Instead, a nerve cell communicates with its target cell across a small gap called a synapse. The ideal treatment for spinal cord injury would stimulate both axon regeneration and the formation of functional synapses with the right target cells. And in humans, that combination of achievements has eluded researchers.


Diagram of a neuron forming a chemical synapse. Nerve cell (neuron) includes the cell body, dendrites, and an axon, a fiberlike extension of the cytoplasm that conducts electrical signals to the next cell across the synapse.

Nevertheless, says Young, recent experiments with adult rats show that some axon regeneration and recovery after severe spinal cord injury might be possible. Although the experiments leave some questions unanswered and it will be important for other groups of researchers to repeat the study, they have generated enormous interest.

"We have been doing this sort of experiment for the past 25 years, but it is only now that something has come out of it," says Lars Olson, see "Swedish Researchers Combine Treatments To Repair Severed Rat Spinal Cords" below) a physician and research scientist at the Karolinska Institute in Stockholm, Sweden, who heads the research team that reported the new results. In their experiments, Henrich Cheng, the surgeon in Olson's group, cut through the spinal cords of adult rats, removed a short segment from each, and grafted into the gap a 'bridge' of 18 tiny pieces of nerve taken from the muscle tissue between the animal's ribs. Cheng added to the graft a mixture of biological 'glue' that contained fibrin (a blood-clotting protein) and a chemical that enhances the outgrowth of fibers from the severed spinal cord axons. After six months, a small number of the spinal cord axons had grown through the graft and the treated animals had regained some ability to move their hind limbs (1).

Newspapers and TV stations reported the new findings with great excitement. "Doctors in Sweden Document That a Severed Spinal Cord Can Repair Itself," read a headline in The New York Times on July 26, 1996. Had Olson and his collaborators done what no other scientists had been able to do?

A panel of neuroscientists who spoke at the annual meeting of the Society for Neuroscience in November, 1996, viewed the Swedish study more cautiously. "The study needs to be replicated independently in another laboratory," says Fred Gage, a neuroscientist at the University of California at San Diego in La Jolla and a member of the panel. Gage agrees that the severed spinal cord axons regrew in the rats. But he is not convinced that those newly formed fibers actually caused the animals' partial recovery of their ability to walk, an issue that he believes can be resolved by more experiments.

Such differences of opinion are not unusual among scientists. Researchers who study spinal cord regeneration approach the problem from many perspectives, and it is inevitable -- and important --that they challenge each other's findings.

In fact, studies of spinal cord regeneration have a long history and embrace many different research strategies. Some scientists want to understand a century-old observation: In a mature mammal, why don't the brain and spinal cord -- which together form the central nervous system (CNS) -- repair themselves following injury or disease? Injured nerve pathways in the adult peripheral nervous system (PNS), which supplies the rest of the body, are often capable of regrowth and recovery. So why doesn't the adult CNS have the same ability?

Other scientists ask why the CNS of a very young mammal can repair itself automatically but the CNS of an adult mammal cannot. Much of their research focuses on the differences between the cellular and molecular environments of the still-developing brain and spinal cord, and those of the adult CNS. For instance, how do the populations of cells differ in the embryonic and mature CNS? What combinations of nourishing proteins, called neurotrophic factors, might very young CNS cells produce that corresponding adult tissues may lack? What protein factors in the adult central nervous system inhibit rather than encourage growth? And how does the extracellular matrix, the noncellular material that lies outside nerve cells, differ in the developing and adult central nervous systems? As scientists learn the answers to these and other questions about the development and function of the central nervous system, they can design strategies for repairing damage to the spinal cord and brain.

Researchers all over the world are trying to find treatments for people who have CNS injuries. Most of them believe that a combination of therapies rather than a single treatment will be necessary, and many teams of scientists are testing experimental treatments in laboratory animals. When will new treatments be ready to test in people?

"I've been asked this question many times," says Young. In fact, Christopher Reeve wanted to know. "I told him that it takes about seven years for any therapy being tested in animal studies to reach humans," says Young. "So Reeve has set a seven-year goal. Seven years has become a rallying cry for research on spinal cord regeneration." The seven years will be up when Reeve turns 50.

Swedish Researchers Combine Treatments To Repair Severed Rat Spinal Cords

In a series of recent experiments, Lars Olson, Henrich Cheng, and Yihai Cao of the Karolinska Institute in Stockholm partly repaired the severed spinal cords of laboratory rats. The researchers used a combination of skillful surgery, grafts of neural tissue from outside the spinal cord, and the addition of nutritive chemical factors to induce some axons of the severed spinal cord to regrow. Rats that received a full combination of treatments immediately after the injury regained some ability to move their hind limbs and support their body weight. Rats that received only some of the treatments did not recover any ability to move.

The Karolinska researchers are now trying to repair the spinal cords of another group of rats that have chronic spinal cord injuries. They are also trying to improve the extent of the rats' recovery by modifying the treatment procedure.


Laboratory rats with severed spinal cords that received a combination of treatments show partial recovery of hindlimb movement. "T8" marks the position of the eighth thoracic segment of the spinal cord, the site of the original surgery.

In their experiments, the Swedish researchers removed a 5 mm segment (less than 1/4 inch) from the mid-thoracic region of the spinal cord of each of 34 rats. An untreated injury in this region would paralyze the animal's hind limbs and cause loss of sensation. But for 22 rats, Olson and his colleagues used a combination of treatments to induce nerve cell axons in the severed spinal cord to regrow across the gap they had created.


(A) Dorsal view of a laboratory rat shows the site of the surgical incision. (B) Enlargement of the rat spinal cord shows removal of a 5 mm segment at T8. (C) 18 tiny pieces of intercostal nerve (from the peripheral nervous system - PNS), acidic fibroblast growth factor (aFGF), and fibrin 'glue' mixture were added to the gap in the spinal cord. (D) Further enlargement of the PNS graft shows the alignment of two (of the 18) fragments of intercostal nerve toward the gray matter of the lower spinal cord stump.

First, the researchers bridged the gap in the spinal cord by grafting into the space 18 tiny pieces of intercostal nerve, which is part of the animal's peripheral nervous system (PNS). Cheng, the surgeon in Olson's group, aligned the minced fragments of intercostal nerve in a precise pattern to ensure that any regenerating fibers would grow into the gray matter of the lower, cut surface of the spinal cord. The gray matter of the spinal cord or brain contains nerve cell bodies rather than axons, which appear white because they are coated with a fatty, insulating substance called myelin.


Myelin wraps around a nerve cell axon in the spinal cord. In the CNS, glial cells called oligodendrocytes produce myelin, which is composed of multiple layers of oligodendrocyte membranes that wrap concentrically around one or more axons. (In the PNS, Schwann cells form myelin.) The myelin sheath around an axon acts like an electrical insulator, allowing nerve impulses to be conducted very quickly. Myelin appears white and shiny because the layers of membrane that form it contain large amounts of fatty substances called lipids.

Second, the researchers applied some biological "glue" into the graft. The glue consisted of fibrin, the sticky protein substance that helps blood to clot, and a nutritive chemical called acidic fibroblast growth factor (aFGF). Other scientists had shown that aFGF encourages damaged axons to regenerate. Cheng also attached wires to the bony vertebrae to stabilize the spinal column as the animals healed.

After just a few weeks, the animals receiving the combination treatment began to show signs of recovery. The researchers measured the recovery process in several ways -- by observing the animals' ability to move their hind limbs and support some of their body weight, and by tracing the regrowth of the severed axons in spinal cord tissue samples obtained from the rats. Other groups of rats served as 'controls' for the experiment. These animals received none or only some of the treatments and showed no recovery.

Many news organizations reported the results of the experiments because they seemed to show that it was possible to induce the injured spinal cord of a mature mammal to regenerate, at least partially. But neuroscientists who scrutinized the study said that it was not possible to determine whether the few spinal cord axons that grew through the graft of peripheral (intercostal) nerve accounted for the animals' partial recovery of movement. They suggested that further experiments would resolve the issue and cautioned that it is still far too early to consider such treatments for people who have spinal cord injuries.

Olson and his colleagues are now conducting the next phases of their experiments. First, they want to learn whether rats with a spinal cord injury induced four months earlier -- in which the researchers also severed the spinal cord and removed a 5 mm segment of it -- can recover after treatment. This "chronic" injury in rats would more closely mimic the kinds of damage that occur in people who have spinal cord injuries, says Olson. In addition to the initial or "acute" injury, all of the secondary events that can cause further damage to the spinal cord tissue would have occurred. (see "What Happens in Human Spinal Cord Injuries?" below)
Second, Olson and his collaborators are trying to improve the extent of each rat's recovery from a severed spinal cord by modifying their treatment procedures in different ways, such as adding different neurotrophic factors. And finally, the researchers are using additional methods to measure the recovery of each rat's ability to move its hindlimbs.

What Happens In Human Spinal Cord Injuries?

Although the spinal cord is protected by the bony vertebrae of the spinal column, it can still be injured ...with disastrous consequences. According to statistics gathered in 1996 by the National Institutes of Health, more than 10,000 Americans experience spinal cord injuries each year and more than 200,000 are living with permanent paralysis in their arms or legs.

People with spinal cord injuries can also lose sensation and -- depending where along the spinal cord the injury occurs -- control over critical body functions, including the ability to breathe. And because two-thirds of spinal cord injuries occur in people who are 30 years old or younger, the resulting disabilities can affect their entire adult lives.

Photo of a car severely damaged in an accident.

Usually, injuries to the spinal cord injuries do not result in a cut through the cord; instead, they crush the thin, fibrous extensions of nerve cells that are surrounded by the vertebrae. These extensions are called axons, the long, thin strings of nerve cell cytoplasm that carry electrical signals up and down the spinal cord. The axons of nerve cells with similar functions run in groups or pathways. Some carry sensory information upward to the brain; others run downward from the brain to control the body's movements. An injury to the spinal cord can damage a few or many of these pathways. Nevertheless, a person can often recover some functions that were lost because of the initial injury.

The damage that occurs to spinal cord axons within the first few hours after injury is complex and it occurs in stages. The normal blood flow is disrupted, which causes oxygen deprivation to some of the tissues of the spinal cord. Bleeding into the injured area leads to swelling, which can further compress and damage spinal cord axons. The chemical environment becomes destructive, due primarily to the release of highly reactive molecules known as free radicals. These negatively charged ions can break up cell membranes, thus killing cells that were not injured initially. Blood cells called macrophages that invade the site of injury to clean up debris may also damage uninjured tissue. Non-neuronal cells including astrocytes may divide too often, forming a scar that impedes the regrowth of injured nerve cell axons.


Micrograph of the spinal cord of an adult rat. As in the human patient, a central cavern (dark) replaces the damaged tissue. A group of descending fibers (white matter) that normally control voluntary movement -- called the corticospinal tract -- ends at the wall of the cavern, indicating that the cavern and its associated scar tissue act as a barrier to regeneration.

The early events that follow a spinal cord injury can lead to other kinds of damage later on. Within weeks or months, cysts often form at the site of injury and fill with cerebrospinal fluid, the clear, watery fluid that surrounds the brain and spinal cord. Typically, scar tissue develops around the cysts, creating permanent cavities that can elongate and further damage nerve cells. Also, nerve cell axons that were not damaged initially often lose their myelin, a white, fatty sheath that normally surrounds groups of axons and enhances the speed of nerve impulses.


A magnetic resonance image (MRI) of the cervical spinal cord of a paraplegic patient showing a cavern (dark area) that has formed at the site of injury. The spinal cord is crushed, not severed, as seen by the continuity of the white matter.

The early events that follow a spinal cord injury can lead to other kinds of damage later on. Within weeks or months, cysts often form at the site of injury and fill with cerebrospinal fluid, the clear, watery fluid that surrounds the brain and spinal cord. Typically, scar tissue develops around the cysts, creating permanent cavities that can elongate and further damage nerve cells. Also, nerve cell axons that were not damaged initially often lose their myelin, a white, fatty sheath that normally surrounds groups of axons and enhances the speed of nerve impulses.

Over time, these and other events can contribute to more tissue degeneration and a greater loss of function. Scientists are trying to understand how this complex series of disruptive events occurs so they can find ways to prevent and treat it. They are also trying to identify treatments that will enhance some of the normal -- but often limited -- kinds of recovery that can occur after a spinal cord injury.

Nerve cell axons in the spinal cord form upward or ascending pathways (blue), which carry sensory information from the body into the spinal cord and brain. The downward or descending pathways (orange) control motor (movement) function. The axons that form the ascending pathways terminate on nerve cells in the sensory region of the cerebral cortex (blue) of the brain. The nerve cell bodies that control movement lie in the motor region of the cerebral cortex (orange) of the brain.

Another complication in spinal cord injury stems from the variety of nerve fibers and cell types that make up the tissue. In the spinal cord, axons run in bundles or pathways up and down the cord. The downward or descending pathways from the brain to the spinal cord carry nerve signals that control voluntary movements. The upward or ascending pathways carry sensory information -- about touch, temperature, pain, and body position -- from the entire body to the brain. Researchers believe that the ascending and descending pathways, as well as different groups of nerve cells (also called neurons) that lie entirely within the spinal cord, may require individualized treatments to regenerate and regain their functions.


A cross-section of the spinal cord shows a different view of the organization of the ascending (blue - sensory) and descending (orange - motor) pathways. At each segment of the vertebral column, the cell bodies of sensory neurons lie outside the spinal cord on both sides in structures called dorsal root ganglia (DRG). The long dendrites of sensory neurons carry information about touch, temperature, body position, and pain from all parts of the body into the DRG. The axons of these sensory (DRG) neurons enter the spinal cord at its dorsal surface, and terminate either in the gray matter of the spinal cord or continue upward into the sensory cortex of the brain. Some axons of sensory neurons form synapses with spinal cord interneurons that send axons into the sensory cortex. The axons of nerve cell bodies that are located in the motor cortex of the brain form the descending motor pathways that synapse in the gray matter (at each spinal cord segment) with the cell bodies of spinal cord motor neurons. The axons of spinal cord motor neurons exit from the ventral surface of the spinal cord and innervate skeletal muscle (in the arms, legs, diaphragm, etc., thereby controlling voluntary movements of the entire body.

"Do the descending motor pathways from the brain into the spinal cord need the same things [for recovery] as sensory fibers that go from the spinal cord to the brain?" asks Barbara Bregman, a neuroscientist in the department of anatomy and cell biology at Georgetown University in Washington, D.C. "It is important to know what the cells need and when they need it."

For example, if scientists are going to be able to devise ways to repair damaged spinal cord tissue, they may need to use special combinations of nourishing proteins -- called neurotrophic factors -- to help damaged axons to regrow and regain some function. The damaged cells may also require a specific environment in which to recover. So researchers study the chemical composition of the non-cellular material -- the extracellular matrix -- that surrounds healthy neurons in the spinal cord and in the peripheral nervous system that serves the rest of the body. Additionally, damaged spinal cord neurons may require the presence -- or even the absence -- of different kinds of non-neuronal cells for regrowth and functional recovery.

Although scientists are beginning to understand the cellular and molecular events that occur after spinal cord injury, one question continues to dominate the research: Why don't the brain and spinal cord repair themselves?

Current Treatment for Human Spinal Cord Injury

What is the best treatment for someone who has just suffered a spinal cord injury? In a recent conversation, Wise Young, who heads the Neurosurgery Research Laboratory at New York Medical Center in New York City, listed the following steps. Young has an 18-year-old daughter and he described what he would do if she were injured.* (The following information is not to be considered as a guide for treating patients with spinal cord injuries. Instead, it is to be used only as a source of information.)


Wise Young, M.D. Dr. Young treats many patients with spinal cord injuries.

Give Methylprednisone

"I would move heaven and earth to make sure that she received methylprednisolone as soon as possible," said Young. The latest studies of the drug, which the federal Food and Drug Administration approved as an emergency treatment for spinal cord injury in 1990, show that it is best to give methylprednisolone within three hours after a spinal cord injury occurs. Patients can benefit from treatment later than that -- up to eight hours after the injury -- but "there's a real need to give it immediately," says Young.

Researchers do not know exactly how methylprednisolone helps injured spinal cord tissue to recover, but they speculate that the drug has at least two main effects. One is that methylprednisolone, which is a synthetic steroid, suppresses immune responses throughout the body. This can be beneficial for patients who have spinal cord injuries because vigorous inflammatory responses at the site of injury may worsen its impact.

The second way in which methylprednisolone works may be to block the formation of free radicals. These charged, highly energetic ions can disrupt the membranes of cells that were not initially injured. So the overall effect of methylprednisolone for people with spinal cord injuries seems to be protective: The drug apparently prevents destructive inflammatory responses at the site of injury and it also prevents the formation of free radicals.

Researchers are continuing to study the effects of methylprednisolone and to design drugs that capture its benefits without causing unwanted side effects, such as too much immune suppression throughout the body.

Remove Any Bone That is Compressing the Spinal Cord

Next, Young would be certain that his daughter received a special operation called "surgical decompression of the spinal cord." In most people who have spinal cord injuries,the spinal cord is compressed, not cut. Thus, the rationale for using surgery to decompress the injured cord is to relieve any pressure from surrounding bone. Pressure on spinal cord tissue can cause mechanical damage as well as cutting off the supply of blood and oxygen.

But the surgery is controversial, says Young, and it is also a difficult and expensive procedure. Young recommends doing the surgery as soon as possible. But he acknowledges that "there are simply no guidelines" for neurosurgeons about when and under what circumstances they should the surgery.

Stabilize the Spine

Young also recommends surgery to stabilize the spine. Stabilization should prevent further compression or twisting of the spinal cord and it should also allow the injured person to be hoisted upright in a specialized bed frame as soon as possible. "The rehabilitation period is much longer if the patient remains lying down," says Young.

Consider Scwann Cell Implants as Experimental Therapy

Of all the experimental treatments for spinal cord injury that researchers are investigating, Young would most seriously consider a Schwann cell transplant.

Dorsal view of spinal cord shows the cervical, thoracic, sacral, and lumbar regions. The arrow at C1-C2 shows the location of Christopher Reeve's injury. The arrow at T8 shows the equivalent position in a human for the experiments in rats that Swedish researchers reported in 1996. Schwann cells are not normally present in the central nervous system (CNS), which includes the brain and spinal cord. Instead, Schwann cells occur in the peripheral nervous system (PNS), which serves the rest of the body. Their function is to produce many layers of a membranous, fatty wrapping called myelin that surrounds nerve cell axons, the threadlike fibers of nerve cell cytoplasm that conduct electrical impulses from a nerve cell to its target. Myelin increases the speed of nerve cell impulses and is necessary for the normal functioning of most nerve cells in the brain and spinal cord.

Researchers consider using implants Schwann cells to help repair damaged spinal cord axons because they may act as a physical bridge, supply nourishing chemical factors that encourage regeneration, and allow the normal functioning of undamaged or regenerated axons. In humans, the procedure would involve removing a small amount of the patient's own peripheral nerve tissue, isolating Schwann cells from the tissue, growing them in plastic culture dishes in an incubator, then implanting the cultured Schwann cells into the site of spinal cord injury.

The strategy of using purified Schwann cells or bits of PNS tissue to repair injured brain and spinal cord axons has emerged from many decades of research on animals. Researchers have learned that by transplanting PNS tissue into the site of an injury in the brain or spinal cord, they can sometimes induce injured CNS axons to regrow. (In fact, the Swedish investigator, Lars Olson, heads a team of researchers who recently reported using tiny bridges of PNS tissue to repair the spinal cords of adults rats.
The transplanted PNS tissue may enhance the regeneration of brain or spinal cord axons for several reasons. PNS tissue -- which includes Schwann cells -- contains nourishing chemical factors called neurotrophins that stimulate axons to regrow. Also, tissue from the peripheral nervous system lacks inhibitory factors that are normally present in CNS tissue and that seem to prevent axon regrowth after an injury. Additionally, the noncellular material -- known as the extracellular matrix -- that surrounds nerve cells has a different chemical composition in the PNS than does the corresponding extracellular material in the CNS. All of these chemical differences -- the combinations of neurotrophins, inhibitory factors, and the composition of the extracellular matrix -- make the peripheral nervous system a more hospitable environment than the central nervous system for axonal regeneration.

Finally, transplanted Schwann cells should help maintain the myelin wrapping that is so essential to the normal function of nerve cells. "Myelin turns out to be a very major factor in spinal cord injury," says Young. Often-- a week or two after a spinal cord injury -- a wave of cell suicide occurs in the CNS cells that make myelin, which are called oligodendrocytes. As a result, the myelin wrapping around the axons of spinal cord nerve cells becomes very thin, which makes the axons incapable of transmitting nerve impulses fast enough to accomplish their normal functions. If another source of myelin -- from transplanted Schwann cells -- could be supplied, the intact and regenerating nerve cells might function more normally.

Begin Rehabilitation As Soon As Possible

Rehabilitation therapy for patients with spinal cord injuries takes many forms, depending on the site and extent of injury and the age and medical condition of the patient.

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Additional Reading:

1. H. Cheng, Y. Cao, and L. Olson. "Spinal cord repair in adult paraplegic rats: Partial restoration of hind limb function." Science 273: 510-513 (1996).
2. W. Young. "Spinal cord regeneration." Science 273: 451 (1996).
3. M. E. Schwab and D. Bartholdi. "Degeneration and regeneration of axons in the lesioned spinal cord." Physiol. Rev. 76 (2): 319-370

Footnote:

* There are no national guidelines for treating acute spinal cord injuries, although many emergency medical teams administer methylprednisolone and stabilize the spine. The treatments described here should not be interpreted as guidelines for medical practitioners. Rather, they are intended to inform readers about existing treatments and potential therapies that may some day be available.