paralysis-lEvery year, television advertising during the Super Bowl serves as a pointer to what Americans are thinking about. One of the more memorable ads from this year’s game featured a computer-generated version of actor Christopher Reeve rising unsteadily from his seat and walking across a stage, to the thunderous applause of the audience. The ad tugs at public compassion for Reeve’s tragic story, shown to us through an avalanche of images over the last decade: early photographs of Reeve, handsome and strong, the actor we all knew as the original Superman; recent photographs of Reeve, calm and determined, and paralyzed from the neck down by a severe spinal cord injury. What the ad suggests is that the seemingly impossible computer-generated dream – Reeve’s recovery from spinal paralysis – might be made possible by scientific research. Recent studies characterizing a group of proteins called neurotrophins suggest that there may be good reason for such hope.

Spinal cord injury is difficult to treat because when spinal neurons are injured or killed, it is difficult to induce them to recover. When we are very young children our bodies are filled with neurons that grow and change, actively shaping the connections between the brain and body. As we mature, the pattern of connections in our nervous system acquires a greater degree of stability, helping us to refine and perfect our muscular control. But if we suffer from a traumatic injury as an adult, the neural stability that helps us refine our control over our bodies becomes a barrier for recovery. In order to heal injured neurons, scientists must figure out what helps neurons grow and change in very young bodies, and how to reactivate those mechanisms to help grown-up bodies recover from neural injury.

axonsEarly Insights
The scientific journey from the molecules that shape the developing nervous system to potential therapies for neural injury follows an interesting path, starting, oddly enough, from a series of Argentinian experiments on snake venom. In 1956, biologist Rita Levi-Montalcini and her American collaborator Victor Hamburger reported that snake venom could induce the tremendous and rapid growth of mouse spinal cord neurons. Somewhere in the stew of chemicals that made up snake venom lurked a promising “nerve growth factor,” a compound that held tremendous potential for therapy and research. Through the hard work of Levi-Montalcini and her colleagues, that factor was eventually purified and characterized. Today, Nerve Growth Factor (NGF) is the archetype of a whole family of neurotrophins, proteins in the nervous system that help regulate neural development and function.

In the half century since the work that initially characterized NGF, the range of its potential applications has only broadened. The earliest studies demonstrated that neurotrophins are driving forces in most aspects of neural development, and more recent studies suggest that neurotrophins might also play a role in the types of neural rewiring associated with learning and memory. Harnessing the power of neurotrophins would provide vast therapeutic prospects for treating spinal cord damage and a whole host of neurodegenerative diseases such as Alzheimer’s or Lou Gehrig’s disease. Perhaps the greatest promise of neurotrophic factors lies in their potential to enhance our ability to learn and to remember.

What is NGF?
The activity of NGF is a gateway to understanding a dominant theme in neural development. In the developing body, the neurons that will connect the brain to skeletal muscles are dramatically overproduced. Over the course of a short developmental period, these neurons compete for limited amounts of trophic factors, a set of neural vitamins without which those neurons would die. Only the cells that receive enough of these vital molecules will survive, a process that helps to refine the brain’s control over the body. The effects of this dramatic competition last long after the developmental period is over; surviving neurons must continually receive adequate quantities of the trophic factors in order to remain alive. In a sense, these neurons are consummately addicted to the trophic factors for their entire lifetime.

While NGF is the predominant neurotrophin in the peripheral nervous system, other members of this family of molecules are dominant in the brain and spinal cord. Neurotrophins like Brain Derived Neurotrophic Factor (BDNF), Glial Derived Neurotrophic Factor (GDNF) and Neurotrophins 3, 4, and 6 (NT-3, NT4, and NT-6) regulate survival and growth like NGF, but these central neurotrophins also have a role in the long-term neural changes in the brain that underlie learning and memory.

The mechanisms of neurotrophins on cell machinery are the subject of vigorous research. One of the more interesting conclusions from the research is that neurotrophins may act as a retrograde signal between neurons. What this means is that neural signaling, which scientists previously assumed was a one way street from one neuron to the next, may actually take the form of a back and forth exchange between neurons. Such changes in the scientific model of neural signaling might open the door for new theories about how the brain works.

Neurotrophins and Disease
The activity of neurotrophins makes them an ideal candidate for therapeutic applications. Since dying neurons in the brain cannot be replaced, treatment options for neurodegenerative diseases like Alzheimer’s and Lou Gehrig’s disease are limited. Recent studies suggest that these diseases act directly on the supply of neurotrophic factors to the affected cells. Administering neurotrophins directly to the affected brain regions, and so enhancing neural survival, has been highly effective in some cases.

Neurotrophins might also be used to facilitate regeneration in cases of spinal cord injury. Peripheral neurons can grow to find their targets over astounding distances, reaching from the spinal cord all the way to the finger tips unerringly. Recently, several researchers have shown that neurotrophins can be used to guide peripheral neurons to targets in the dorsal root of the spinal cord. The problem of regeneration in the central nervous system is more difficult, but the future of such research is promising.

Despite the tremendous progress in basic research, viable clinical applications of the neurotrophic molecules have yet to develop. Much of the problem lies in the very nature of working with human subjects. Basic research is typically done using animals, because animal experiments provide far more insight into the mechanisms underlying neural function than human studies could. One of the issues that arises when moving from animal experiments to human trials is dosage. Without an appropriate dosage, the effects of neurotrophins are likely to be unpredictable. Too little neurotrophin is ineffective, but with increasing dosage come negative side effects; for example, a consequence of too much NGF is significant pain. For this reason, the therapeutic dosages are often much less than those proven to be effective in animal models. Delivery is also a complex issue; neurotrophins do not cross the blood-brain barrier, and it is difficult to target the effects of a direct injection into neural tissue. Many pharmaceutical researchers are hard at work on these problems, however, and as the mechanisms of neurotrophic action are elucidated, more effective solutions will become possible.

One case in which a neurotrophin is already used effectively is diabetic neuropathy. In this disease, the degeneration of neurons associated with certain forms of diabetes can be slowed using the original Nerve Growth Factor discovered by Levi-Montalcini. Diabetic neuropathy has wide ranging symptoms, including ulcers, pain, sensory loss, and weakness, and the use of NGF to combat the disease represents a significant therapeutic breakthrough. The key to further progress lies in basic scientific research on the mechanisms of neurotrophic activity. With continued basic research and clinical innovation, the promise of neurotrophins could be realized in the next half century.