From ancient Egypt to present day: SCI research

Throughout most of scientific and medical history, spinal cord injury and paralysis have been considered irreversible and untreatable. As far back as ancient Egypt, physicians believed that there was nothing they could do to help the person with spinal damage. Even as our understanding of the nervous system and its function deepened over the years, the belief persisted that nerves in the central nervous system (CNS, i.e. brain and spinal cord) simply could not regrow once injured.

Only in the past 35 years or so this dogma been fully put to rest. It has long been known that damaged peripheral nerves, those in the body, are capable of regeneration and can be restored to full function. Scientists wondered what was special about the peripheral nerve environment.

In the 1980s, experiments in rats showed that central nervous system cells could regrow their nerve fibers, or axons, under laboratory conditions that mimicked the peripheral nervous system (PNS).

Why? Partly because the PNS environment provides certain nutrients that CNS axons like, and partly because the CNS environment contains molecules that are actively hostile to nerve repair.

Researchers began to identify the exact molecular conditions that encourage axons to regenerate in the living body. They also discovered the factors that prevent CNS axons from regrowing. In the late 1980s, the first of these roadblocks was identified: powerful regeneration-blocking proteins produced by the myelin sheath that wraps the nerves of the central nervous system. By removing the blocking proteins, axons were able to grow quite robustly.

This discovery injected new life into a field that had been dismissed as hopeless, and ushered in a new era of research across the full range of spinal cord biology.

Neuroprotection

1990s: Scientists learned that trauma to the spinal cord occurs as a lengthy cascade of damage.

First is the impact that injures the cord, followed by a sequence of cell damage related to inflammation and chemical chaos at the lesion area. One drug, a steroid, has been approved for acute SCI; this occurred in 1990.

Today: Work continues to develop an effective acute treatment for spinal cord trauma, with a much better understanding of the molecular environment after injury, including new discoveries about the role of glia, blood pressure, and immune response.

Numerous clinical trials are underway to test drugs, cooling, or cell therapies that have been shown to minimize nerve damage and preserve function in animal studies.

Promoting axon growth

1990s: Scientists began to treat nerve trauma with substances that either promoted axon growth directly or blocked growth-suppressing molecules. These strategies were successful for reviving individual injured neurons and, in animal models, they also led to a partial recovery of spinal cord function.

Today: Scientists continue to modify the CNS environment to make it more hospitable to growing neurons. A number of intrinsic molecules have been identified that either promote or repel growth, as well as a number of growth promoting molecules have been identified and continue to undergo testing.

An exciting new area of research has shown that a damaged axon itself is unable to mount a vigorous response to injury. By understanding the body’s genetic codes related to embryonic development, scientists have been able to reboot the body’s response to injury, thus engineering unprecedented axon growth. While an important development, this avenue of pursuit requires more study.

Simply regrowing a damaged axon is not enough to restore neuron function. The growing axon also has to be nourished and supported, and then connected to a target that produces useful function, and not pain or spasticity.

Enhancing compensatory growth

1990s: Scientists noticed that treatments designed to repair damaged axons also helped healthy surrounding neurons to grow and support the recovering cells.

Today: Researchers are working on tailoring this process to rebuild damaged but intact neuronal networks, particularly in people with incomplete spinal cord injuries -- those who still have uninjured nerves that might be coaxed into taking over the function of the damaged ones.

Plasticity

1990s: Until the early 21st Century, the basic dogma held that the nervous system is a single set of “wires,” formed in development and are then static across the lifespan.

Today: Scientists know now that the brain is not hardwired; it does in fact create new nerve cells in adulthood. Moreover, there are ways to manipulate or enhance neuronal growth. Injury results in major nerve remapping to adapt to signal disruption. Spinal cord circuits are plastic, that is, they can be trained to take over function in damaged areas. Simple therapies such as intermittent hypoxia or physical exercise appear to promote the outgrowth of certain nerves linked to motor function.

Scientists are studying various drug therapies that might boost neurogenesis and plasticity. There is evidence that mindfulness itself can affect plasticity related to memory and cognition. There is tremendous excitement about using electrical stimulation of the brain or spinal cord to enhance motor function by increasing plasticity.

The minute circuitry of the spinal cord is not fully understood but promises to yield more precise therapies that will encourage repair and plasticity, tailored to the specific needs of individuals with paralysis.

Glial cells

1990s: Scientists were just beginning to understand that astrocytes and oligodendrocytes are not static or passive space fillers in the nervous system.

Today: The role of these nervous system helper cells continues to unfold. Astrocytes are now known to play a crucial role in response to nervous system injury -- in good ways, by nurturing neurons, and bad, by creating scars that seal off areas of injury.

Oligodendrocytes are key to the formation of myelin, the insulation on nerve axons that allow electrochemical signals to speed along. Loss of myelin (also the defining feature of multiple sclerosis) appears to be treatable by way of cell therapies.

Preventing scar formation

1990s: Scar tissue at the site of the spinal cord injury acts as both a physical and a chemical roadblock to repair. In the 1990s, researchers pinpointed some of the growth-blocking molecular signals related to scar tissue and started looking for ways to overcome those inhibitory messengers.

Today: Researchers are testing enzymes that essentially dissolve the scar and allow nerves to cross its barrier. In laboratory studies, animals have regained function after application of scar-busting drugs. Human trials are planned once technical details are worked out.

Artificial bridges

1990s: Axons need a solid base upon which to grow. They are unable on their own to span the physical gap at the site of spinal cord lesion. In the 1990s, researchers began to test engineered materials that could help neurons cross these breaks. They also found that certain kinds of transplanted cells could bridge the gap. Transplanted supporting cells, such as Schwann cells and olfactory ensheathing glia (OEG), taken from the body of a test animal, showed great potential.

Today: Investigators have developed synthetic polymer scaffolds and organic substances (i.e. fish fibrins) as a gap-spanning alternative to living cells.

These scaffolds provide a physical support for growing cells, but could also be combined with growth-promoting molecules, or even stem cells, to promote recovery of function.

Researchers are working to improve the success of transplantation of specialized cells. Animal experiments have encouraged clinical trials. Schwann cells and OEG transplants have already entered human trials, as have several types of stem cells. Some trials are enrolling people with long-term injuries which is particularly encouraging.

Stem cells

1990s: Scientists learned how to isolate human stem cells and began transplanting these cells in animals to attempt to rebuild the damaged neural circuitry. They hoped that the undifferentiated cells could migrate to where they were needed and change into the missing cell types. There was a lot of hype in which the public lauded stem cells as “nature’s toolbox” that could fix any problem in the body.

Unfortunately, many people were attracted to overseas clinics promoting stem cell magic without sufficient scientific and clinical evidence to back up the claims.

Today: The great promise of stem cells is slowly being realized. There are a number of clinical trials underway to test these cells for a variety of conditions, including spinal cord injury – both acute and chronic.

Stem cell scientists have discovered new cell forms, including induced pluripotent cells (iPSC), which is a cell from the body, a skin cell for example, that can be programmed to a more primitive state. These iPSC behave very much like undifferentiated stem cells, and without the ethical issues related to embryonic cells.

Redesigning rehabilitation

1990s: The SCI field was just beginning to understand that rehabilitation was more than offering compensatory devices and tools. The importance of physical therapy in spinal cord injury rehabilitation was established, underscored by animal and human studies that showed repetitive and structured stepping routines could encourage the lower spinal cord (below the area of the injury) to actually "learn" how to control movement without input from the brain.

Scientists also found that activity-based therapies heightened the body's production of molecular signals that support axon growth and neuron survival.

Today: Vigorous exercise has become a standard part of rehabilitation. Scientists have come to understand that certain forms of patterned activities awaken dormant nerve circuits in the spinal cord, and can trigger some degree of function.

This is the basis for neurorecovery related to locomotor training -- stepping with assistance on a moving treadmill. Taking this a step further, researchers have added spinal cord stimulation to activity. In a small number of patients, spinal cord stimulation has produced unprecedented recovery of function; moreover, the stimulation produces residual benefits in cardiovascular, bladder and sexual function. More human trials are on the way.

Exploring the genetic frontier

1990s: Scientists began to study the genetic basis of how the brain and spinal cord are formed.

Today: Researchers have a better understanding of developmental biology and the specific genes that make up the blueprints for forming our nervous systems before we are born.

Scientists now believe it is possible to switch on gene targets to promote nerve growth in an adult animal. Using sophisticated micro-array screening techniques, and data from mouse and human genome analysis, we now have a better understanding of the body’s genetic codes for cell activity and behavior related to axon regeneration.

Other modern research ideas that were not in play 25 years ago

Combination therapies: It is likely that no single therapy will provide a cure for spinal cord injury. Rather, a combination of therapies, over time, may be required.

Brain-machine interface: In the past ten years or so bioengineers have been able to harness brain waves in animals, including humans, to control computer devices.

For example, a rhesus monkey, using only his mind, was able to precisely activate the paralyzed hand of a partner primate. A quadriplegic woman, using only her thoughts, piloted a fighter jet simulator. A quadriplegic man, directing thought to a prosthetic arm, was able to grab a glass of beer and drink it. This area is moving very fast in numerous labs.

New tools: Scientists now have ways to observe nerve function in living animals. New tools, including optogenetics, can turn individual cells on and off using a light source. New methods for manipulating or even editing genetic codes are now available.

Big Data: The SCI field is now fully engaged in bioinformatics. The analysis of so-called Big Data allows researchers to mine vast amounts of research data for patterns and details at levels not possible before. Moreover, the field has made great strides toward standardizing the way experiments are performed to speed discoveries and reduce repetition.

Metrics: To test the effect of a therapy, researchers have devised very precise ways to consistently and accurately measure any changes in function. These include series of tests for hand and finger function for any therapy directed toward cervical injury. Appropriate and sensitive outcome measurements are critical to the planning and execution, and ultimately the success, of clinical trials.