Behind the scenes of scientist's dream to cure paralysis

[Max]

Behind the scenes[italic off] of scientist's dream[italic off] to cure paralysis[italic off]
By Bill McClellan
12/15/2002 12:00:00 AM



Dr. John McDonald of Washington University became famous this fall. He is the man behind the Superman Miracle. He designed the exercise regimen that helped Christopher Reeve regain some movement in his hips, fingers, wrist and feet - seven years after the actor was thrown from a horse and paralyzed below the shoulders.

That kind of progress so long after an injury was completely unexpected, and McDonald, 39, became a symbol for new ways of dealing with this kind of trauma. In fact, I heard him on the radio Friday afternoon. The show was Science Friday on National Public Radio, and the topic was spinal cord injuries.

Mostly, the talk was about Reeve, and his exercise regimen, and the philosophy that underlies it - nerve cells can regenerate.

Apparently, that is revolutionary thinking, but the truth is, McDonald's work with Reeve is downright pedestrian compared with the things he's working on as director of the spinal cord injuries center at the Washington University School of Medicine.

I visited the center Friday morning. There are three floors where practical, real-life medicine is practiced. There are patients' rooms on the second and third floors, and in addition to the hospital rooms, each floor has two apartments where patients are moved before they're sent home.

"The hospital rooms are designed for our patients," said Linda Schultz, the nursing specialist for the center. "They are completely accessible. You can wheel a chair into the shower. But what happens when that person goes home and has to use a bathtub? That's why we have the apartment units, to help patients get adjusted to normal conditions."

Each of the first three floors also has a therapy area. The one I visited Friday morning was very busy. I saw a man pedaling a stationary bicycle. Like Reeves, he was paralyzed from the shoulders. (The stationary bike was, and still is, a big part of Reeves' exercise regimen.) How does someone who can't move his legs operate a bicycle? Electrodes are attached to his thighs, hamstrings and gluteal muscles. The electrical impulses stimulate the nerves. Not only is this good cardiovascular exercise, but McDonald believes it stimulates nerve regeneration.

He has a lot of ideas, and on this morning, it seemed that each patient reminded him of some theory, either outdated or just coming into acceptance. He pointed at a young man lying on a massage table. Look at his leg twitching, McDonald said. We used to medicate to inhibit spasticity, but now we believe that the medication inhibits recovery. A 53-year-old truck driver, who suffered a broken neck and a broken back in an accident three months ago, has already regained partial use of his legs, and that reminded McDonald of a now-discarded theory about age and recovery, and a new theory about regeneration.

All of this up-to-date medicine is impressive, but the real heart of the program is on the fourth floor. That's where the labs are. And forget up-to-date. The fourth floor is way past that. It's somewhere in the future.

McDonald is working with embryonic stem cells from mice. He put a tissue culture under a microscope and talked excitedly about neurons, astrocytes and oligodendrocytes. That might mean as little to you as it does to me, but the gist of it is this: McDonald has been growing nerve cells. He has cured mice with spinal cord injuries. He has transplanted mouse cells into rats, and those nerve cells have functioned.

If this work pans out, it will have ramifications not only for people with spinal cord injuries, but for people with MS, Parkinson's and ALS.

By the way, the tour Friday morning wasn't just for me. McDonald was recruiting a young scientist, and the young man was clearly impressed. So was I. How often do you see people working on a miracle, and in the same building, one and two floors below, the very people who pray for one? E-mail: bmcclellan@post-dispatch.com

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[Schmeky]

McDonald's application of physical activity in an attempt to regenerate the spinal cord is not new, but it is practical. This is the rational I base my decision on for attending Project Walk. However, I wonder how many labs are doing parallel research on stem cells, like McDonald is currently doing? In addition, how many more damn rats have to be injured/treated/cured before humans can recieve treatment? Why doesn't some foeward thinking, futuristic group go to bum-fart bohemia where there are no restrictions/regulations and perform what appears to be a well proven and thoroughly tried rat procedure on a human volunteer? If successful, the SCI world would be in high gear and the cure pendulum would swing resoundingly in our direction. Nothing happens without taking a risk, breaking a rule, or crossing a boundary line.

[DA]

dr young....dr mcdonald making you look bad. he is stealing your spot light. what are you going to do?

[Iacopo]

excerpt from above:

"We used to medicate to inhibit spasticity, but now we believe that the medication inhibits recovery."

This concerns Baclofen. Not only may this widely used drug inhibit recovery, but it may also inhibit regeneration through multiple mechanisms, as noted in the following:


Bird M; Owen A; Neurite outgrowth-regulating properties of GABA and the effect of serum on mouse spinal cord neurons in culture. J Anat 1998 Nov;193 Time-lapse photography was used to examine the effects of gamma-aminobutyric acid (GABA) on the outgrowth and motility of neurites in cultures from mouse spinal cord. GABA at concentrations of 100, 10 and 1 microM caused significant inhibition of neurite outgrowth and the motility of growth cones was significantly reduced by treatment with 100 and 10 microM GABA. This effect was mimicked by the GABA(B) receptor agonist baclofen, whereas the GABA(A) receptor agonist muscimol had no effect. The effect of GABA on outgrowth and motility seems to be dependent on the type of serum employed. The results reported here were obtained only when heat-inactivated serum was used and not when non heat-inactivated serum was added to the culture medium. They suggest that GABA has a role in the regulation of process outgrowth within the embryonic mouse spinal cord.


Xiang Y, Li Y, Zhang Z, Cui K, Wang S, Yuan XB, Wu CP, Poo MM, Duan S. Nerve growth cone guidance mediated by G protein-coupled receptors. Nat Neurosci 2002 Sep;5(9):843-8 Growing axons navigate by responding to chemical guidance cues. Here we report that growth cones of rat cerebellar axons in culture turned away from a gradient of SDF-1, a chemokine that attracts migrating leukocytes and cerebellar granule cells via a G protein-coupled receptor (GPCR). Similarly, Xenopus spinal growth cones turned away from a gradient of baclofen, an agonist of the GABA(B) receptor. This response was mediated by G(i) and subsequent activation of phospholipase C (PLC), which triggered two pathways: protein kinase C (PKC) led to repulsion, and inositol 1,4,5-triphosphate (IP(3)) receptor activation led to attractive turning. Under normal culture conditions, PKC-dependent repulsion dominated, but the repulsion could be converted to attraction by inhibiting PKC or by elevating cytosolic cGMP. Thus, GPCRs can mediate both repulsive and attractive axon guidance in vitro, and chemokines may serve as guidance cues for axon pathfinding.


Min MY, Appenteng K, Yang HW. Role of GABA(B) Receptor in the Regulation of Excitatory Synaptic Transmission in Trigeminal Motoneurons. J Biomed Sci 2002 Jul-Aug;9(4):348-58. The aim of the present study was to determine if excitatory synaptic transmission onto trigeminal motoneurons is subject to a presynaptic modulation by gamma-aminobutyric acid (GABA) via GABA(B) receptor in this system. Whole cell recordings were made from trigeminal motoneurons in longitudinal brain stem slices taken from 8-day-old rats. Monosynaptic excitatory postsynaptic potential (EPSP) activity was evoked by placing bipolar stainless steel electrodes dorsal-caudal to the trigeminal motor nucleus. Bath application of the GABA(B) receptor agonist, baclofen, produced a marked reduction in the mean amplitude and variance of evoked EPSPs and also increased the portion of transmission failures. It also produced a decrease in the frequency, but not in the mean amplitude, of spontaneous miniature EPSPs. Bath application of GABA(B) receptor antagonists 6-hydroxy-saclofen and CGP35348 increased both the amplitude and frequency of miniature EPSP activity. Taken together the above results suggest that the excitatory synaptic inputs onto trigeminal motoneurons are controlled by tonic presynaptic modulation by GABA(B) receptor. Copyright 2002 National Science Council, ROC and S. Karger AG, Basel


Alford S, Christenson J, Grillner S. Presynaptic GABAA and GABAB Receptor-mediated Phasic Modulation in Axons of Spinal Motor Interneurons. Eur J Neurosci 1991;3(2):107-117. The lamprey spinal cord has been utilized to investigate the role of presynaptic inhibition in the control of the spinal motor system. Axons of the lamprey spinal cord are comparatively large because of their lack of myelination. Axons impaled with microelectrodes demonstrate depolarizing responses to the application of GABAA and GABAB receptor agonists, muscimol and baclofen. These depolarizing effects are counteracted by the specific GABAA and GABAB receptor antagonists, bicuculline and phaclofen. GABAA receptor activation leads to a gating of Cl- channels on the axons. However, the ionic mechanism leading to axonal depolarization following GABAB receptor activation is unknown. After initiation of fictive locomotion, these axons demonstrate oscillations in axonal membrane potential related to the locomotor cycle. During ficitive locomotion they depolarize in phase with the bursting of the ipsilateral ventral root of the same segment. These axonal membrane potential oscillations are due to a phasic GABAA and GABAB receptor-mediated gating of ion channels on the axonal membrane. Fictive locomotion in the lamprey spinal cord is largely unaffected by antagonism of one or other GABA receptor subtype alone, but is severely disrupted by simultaneous antagonism of both subtypes. In conclusions, we demonstrate, for the first time, an agonist-gated depolarization of a vertebrate presynaptic element measured by direct impalement of the axon under study. We also demonstrate that GABA-mediated presynaptic inhibition occurs in axons of spinal interneurons. It is not limited to the primary afferents as has previously been believed.


Moran JM; Enna SJ; McCarson KE; Developmental regulation of GABA(B) receptor function in rat spinal cord. Life Sci 2001;68(19-20):2287-95. GABA(B) receptors are heterodimers coupled to G-proteins. The present study was undertaken to investigate activation of GABA(B) receptors in cerebral cortex and spinal cord using [35S]GTPgammaS binding assays, a direct measure of G-protein activity. The results revealed that the GABA(B) agonist baclofen stimulates GTPgammaS binding in cerebral cortex, with an ED50 of 50microM. This response is blocked by the GABA(B) receptor antagonist CGP 55845A (100nM). In contrast, baclofen-stimulated GTPgammaS binding was not observed in adult spinal cord tissue under similar incubation conditions, or after varying magnesium, calcium, GDP, [35S]GTPgammaS, or membrane concentrations in the assay medium. Stimulation of adult rat spinal cord muscarinic receptors did result in a concentration-related increase in [35S]GTPgammaS binding. Baclofen-stimulated GTPgammaS binding in adult spinal cord did not appear after peripheral inflammation, despite significant increases in GABA(B) subunit mRNA levels. As opposed to adult, appreciable GTPgammaS binding was observed in membranes prepared from spinal cords of rats within the first 14 days of postnatal development, suggesting that GABA(B) receptor function in the rat spinal cord is developmentally regulated. The results indicate that GABA(B) receptors may not be coupled to G-proteins in the adult rat spinal cord, or couple in a way that differs from that in newborns or adult cerebral cortex.