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Paralysis, Memory and Learning: Do Our Bodies Hold the
Promise of Regeneration?
by Kumar Narayanan
Every 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.
Early 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 LeviMontalcini 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.
Neurotrophins help many neurons to survive and grow. In this example,
the neurotrophin dramatically increases the number and length of the
neuron's dendrites. More dendrites might allow the neuron to make
additional connections with other neurons, and that type of change
may underlie nerve repair as well as some types of learning and
memory.
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.