Are you wired?

That is, are you wearing a hidden recording device? Or are you well-connected with higher-up or important people? Or are you merely reveling in an adrenaline rush?

Those informal terms aside, all of us vertebrates are doubly wired. We make do with two nervous systems - one central (CNS), the other peripheral (PNS). CNS comprises brain coupled to spinal cord. PNS picks up where CNS leaves off, with cranial, spinal, sympathetic and parasympathetic nerves.

What both these hard-wired nervous systems have in common is myelin. This fatty, proteinaceous, membranous sheath wraps around the axons of nerve fibers, much like insulation around a wire. When CNS neurons shed or lose some of their myelin, those axons can no longer conduct the action potential - the electrical signal - that keeps them in business.

When this happens in the central nervous system, it causes multiple sclerosis, a paradigmatic demyelination disorder. "When axons in the peripheral nervous system's neurons lose their myelin," observed neurobiologist Eric Shooter, "a whole group of diseases can be affected - for example, Guillain-Barré syndrome. These are the principal sensory and motor fibers that go from the spinal cord down to the leg muscles and on to the nerve endings of the feet. For lack of myelin wrapping," Shooter continued, "their nerve cells' electrical signals falter, their connections to muscles weaken, and the muscles atrophy. There's a broad range of expression in those diseases - good or bad," Shooter added. "An affected individual can go from feeling very little effect on the leg muscles, so all he does is trip around a bit, to becoming completely paralyzed, and permanently wheel-chaired."

Shooter, a professor of neurobiology at Stanford University, focuses his research on seeking therapies to prevent or reverse demyelination, primarily in the PNS. He is senior author of a paper in Science dated Nov. 8, 2002, titled: "The neurotrophin receptor p75^NTR as a positive modulator of myelination."

Pinning Hopes On Brain-Derived Nerve Factor

"We discovered a new function for the neurotrophins, which are the original PNS nerve growth factors," Shooter told BioWorld Today. "That function would be to elucidate how myelin is formed in the peripheral nervous system. So our paper adds one more set of factors to that whole equation. This is a new one.

"The key point about our Science paper," he continued, "is that the effect on the neurotrophins of BDNF - the brain-derived neurotrophic factor - occurs through the second of the two neurotrophin receptors. That second receptor, P75, which we originally cloned, is the receptor that binds all the neurotrophins. Others have been searching for a function for it for years. They've been dropping out, so here is one more neurotrophin. Acting through this particular P75 receptor, P75 promotes myelin and enhances myelination. It gives a potential clue toward therapies, which are really needed for this whole group of diseases of the demyelinating PNS neuropathies."

In pursuit of therapeutic goals, Shooter and his co-authors embarked on a series of in vitro and in vivo experiments. "The first techniques that we used," he recounted, "were co-culture systems where we could take axons and add to them Schwann cells, and make those PNS cells do their job of producing myelin. In that culture system we could actually ask what compounds would enhance or inhibit myelin formation. And that's how we found BDNF enhancers, and the other neurotrophin NT3 inhibitors.

"We then moved from in vitro to in vivo," he went on. "We simply injected BDNF subcutaneously into one leg of a newborn mouse. The BDNF diffused over to the sciatic nerve, and amazingly had exactly the same effect in the nerve as it did in co-culture. So we used a neonatal mouse to show that this is a real property of BDNF, which works in the whole animal.

"The other thing we did," Shooter went on, "was to determine that P75 was the key receptor. We got hold of knockout mice that had been engineered to lack the P75 receptor. And what we found then was that with no P75, BDNF had no effect at all on myelination - either positive or negative. The reason? Those mice had lost the key receptor that was doing its job. It's a nice use of these transgenic animals. Without the gene coding for P75, we could now show very directly that with complete loss of BDNF's action it must work through P75."

Transgenic Mice Stand By To Test Likely Drugs

"And now we're starting on other transgenic neuropathies," Shooter allowed. "There are two mice, called Trembler J and Trembler, which make perfect animal models for particular human patients with peripheral neuropathies. They harbor the same mutation in one of the myelin proteins that these mice have. We're just starting on these perfect animal models. We don't have any data at the moment. Our hope is that BDNF would either slow down demyelination or turn it around and make these animals remyelinate. And that's where we are at the moment, trying to do that."

Shooter said, "We can now make any mouse model we want of a PNS neuropathy - not a difficult thing to do - and use them in the first instance to test out therapeutic drugs and small molecules. And for any that work in mice we can move into the human condition." Shooter disclaims any likelihood of a successful outcome. "We have no idea," he said. "I know enough about biotechnology to realize that what works in the mouse doesn't necessarily work in the human."

On this theme he recalled, "I was a co-founder of Regeneron Pharmaceuticals Inc. [Tarrytown, N.Y.] in 1990. There we tried this famed BDNF, which in mice promotes neuronal survival in models of motor neuron diseases. But at Regeneron it failed to do that when we moved into Lou Gehrig's disease in humans. It failed because it made most patients lose weight. So Regeneron has now turned that compound back around and is testing it as an obesity drug that makes people lose weight. Quite a big clinical trial on it is going on right now," he concluded, "which you may hear about next year."