It’s an old, grim axiom of neuroscience: After an injury, the nerves in your hand, arm or leg may grow back, but neurons in the brain and the spinal cord will not.

Part of the reason is a molecule called proteoglycan — a biological insulation that separates tissues. During gestation, for example, proteoglycans prevent the placenta from growing too deeply into the uterus. “The proteoglycan molecule has been known as nature’s own barrier molecule,” says Jerry Silver, a professor of neuroscience at Case Western Reserve University.

Proteoglycan strongly inhibits the growth and movement of cells, and explains why cartilage has neither nerves nor a blood supply.

In the spinal cord, proteoglycan serves to lock the nerves into position, preventing unwanted growth. Unfortunately, when the spinal cord is injured, a new burst of proteoglycan “walls off the injury site, but also blocks nerve regeneration,” says Silver.

A bacterial balm?

Now, using an enzyme made by a deadly bacterium, Silver and his colleagues have learned to restore normal breathing in rats with a damaged spinal cord. The study, published in Nature yesterday, shows that a combination of grafting and a proteoglycan-eating enzyme called chondroitinase may sidestep the proteoglycan’s growth-deadening effect – and open a path to the holy Grail of partial repair to the spinal cord.

As scientists continue trying to rebuild the spinal cord with stem cells, the new study shows an alternative route to healing.

The technique is rooted in evolution, Silver says. “Proteoglycans are boundary molecules that have evolved over millennia. One bacterium, proteus vulgaris knows that, and has figured out how to release this enzyme to eat through our defenses.”

That ability allows the bacterium to cause deadly septic shock.

What they did

To demonstrate that grafts plus chondroitinase enzyme could restore function, Warren Alilain, the paper’s first author:

It’s important to realize that when the graft was first connected to the spinal cord, it no longer contained neurons. The graft serves as a tunnel lined with cells that supply growth factors and nutrients to nerves that are growing from the upper part of the spinal cord.

The wait for recovery seemed interminable, Silver admits. “Warren Alilain, my genius post-doc, had given up, he saw no substantial return of function at two months … but at 10 weeks, he ran into my office, he saw some activity coming back.”

After another two weeks, the disconnected nerves had regained at least 80 percent of their normal electrical output in 9 of the 11 animals that got grafts and enzyme.

Spinal cord: A brainy organ?

Just getting neurons to grow in the central nervous system is not enough: the nerves must connect to the motor nerves that activate the diaphragm. After all, the spinal cord contains more than ten thousand nerve cells, and neurosurgeons cannot hope to connect them individually; and instead want to coax a process of self-connection.

The coaxing worked: among about 3,000 spinal-cord neurons that grew through the graft tube, 400 to 500 linked to the neurons that used to control the diaphragm. In other words, the growing neurons seem to be “looking” for precisely those nerve cells that must be reconnected so the diaphragm can return to work. The spinal cord, Silver says, is “smart, and that’s encouraging news. I am more optimistic than I have ever been: The gain in function is really high.”

Yet despite the crying need for better treatments for spinal cord injury, at best this technique will not be available for some years.

The technique seems unlikely to restore the complicated connections needed for walking or typing, but severe paralysis would be eased just by activating a single muscle, Silver says. Bladder control is a major issue after a lower spinal injury, and many quadriplegics require a ventilator, which can fail or cause deadly infection. Learning to reactivate the diaphragm – and to breathe — could produce huge gains in quality of life.

Courtesy Jerry Silver, Case Western Reserve University

Enzyme and graft treatment each restored nerve function in most of the rats, but the best response came from a combined treatment.

“This is an interesting study,” says Daniel Resnick, associate professor of neurosurgery at University of Wisconsin-Madison. “It’s a fairly vigorous model, measuring the diaphragm motion is a fairly clean measure.” Not only did the grafting process restore fairly normal breathing, but when the researchers cut the nerve graft at the end of the experiment, that removed the improvement in breathing. “That’s pretty convincing evidence that you have got neurons growing through the graft.”

The repair was not a true replacement for the spinal cord, Resnick adds. “They are not regenerating across the injury itself, but are by-passing it, going directly to the muscle. It’s not a cure for a spinal cord injury, but is a means to promote focal re-enervation, but for a high spinal cord injury, if you could get them off a ventilator, that is a big deal.”

Silver says the data also suggest that the bacterial enzyme may in some cases be effective enough to avoid grafting. “I am enthusiastic about using just the enzyme, in spinal cord injury and stroke rehabilitation,” Silver says. “Given the success to date – in our lab and others — it’s simple to do and seems to carry almost no risk — it’s just putting in a shot of enzyme as a way of stimulating neural plasticity.”

– David J. Tenenbaum

Wondrous weevils sport super screw!

In animal appendages, some joints resemble hinges. Others, like your hip, are unmistakably akin to the ball-and-socket joint, another mechanical mainstay.

Now, scientists have found a biological screw in a type of beetle called a weevil. Obliquely described as having “rotational movement combined with a single-axis translation,” the new screw-and-nut assembly was first seen in a weevil from New Guinea, says entomologist Alexander Riedel.

The discovery of the first biological screw-and-nut assembly emerged from an exploration of the weevil’s characteristic defense mechanism, says Riedel, an entomologist and curator who specializes in weevil classification at the State Museum of Natural History in Karlsruhe, Germany.

Two things weevils have in common are small size – the Trigonopterus oblongus under study was about 4 millimeters long – and legs that fold under the body. “We wanted to look at their particular defense mechanism,” says Riedel, “to know how it works.”

Using a microscopic counterpart to CT scanning, German researchers snapped electron micrographs of the weevil’s trochanter (“screw”) and (ROLLOVER) coxa (“nut”).”

Image © Science/AAAS

It’s all in the scan, man!

Given the small size, the scientists relied on a kind of micro CT scan driven by X-rays from a synchrotron, “We realized there is a very nice screw joint,” Riedel says, “We’ve had this information for some time, but while talking with a herpetologist colleague, we realized there is no other case in the whole animal kingdom, in all of biology, with a similar screw joint.”

The nut-and-screw are located at one of three major joints in the beetle’s leg; when the leg is retracted, the screw tightens in the nut, which remains stationary, Riedel says. Overall, the screw and nut would be able to turn 345 ° although the leg itself does not move that much.

A (good) turn of the screw!

“The weevils, or snout beetles, have been known from ancient times,” says Riedel. “There are grain weevils and lots of other species, including the boll weevil [a cotton pest]. Many other species are not pests … and so are of no particular interest to humans, which is why nobody knows much about them.”

Why does every weevil species that that Riedel examined have such a mechanism? Weevils, which spend a lot of time climbing on vegetation, apparently evolved from beetles that usually walk on a flat surface or underneath bark, Riedel says. “If a weevil is sitting on the edge of a leaf and wants to walk on a small twig, it’s essential that it can grip under its body, and this motion goes very nicely with this screw joint. A ground [walking] beetle would have great difficulty walking in similar conditions.”

The screw joint now joins the hinge, ball-and-socket and saddle joint as fundamental technologies invented by evolution, Riedel says. Historians of technology have long wondered about the origin of the incredibly useful screw, and it turns out that screws and nuts were in their flour bins all along – but only visible to those who happened to have a handy synchrotron!

– David J. Tenenbaum

Strokes — bleeding or blocked blood vessels in the brain — are a major cause of disability, and most neuroscientists say the brain has little or no ability to repair itself afterwards: Dead neurons do not spring to life. They are not replaced, and losing the ability to talk to each other is irrevocable.

Photo: University of Cincinnati

Relearning the activities of daily life can be a struggle after a stroke. The University of Cincinnati has tested a robotic brace to aid recovery. A drug that restores brain cells could reduce the need for this kind of retraining.

When a stroke cannot be prevented, damage is irreversible. Or so went the neuroscientific dogma.

But a mouse study being published today in Nature shows that suppressing a common brain chemical can boost neuronal repair after a stroke. The treatment focuses not on restoring neurons, but rather on restoring connections, so neurons located at the edge of the dead zone can talk to each other and go back to work.

Based on tests of walking ability, the mice regained 30 to 50 percent of their motor coordination. If this result can be repeated, it could represent a major step forward, as no drug is approved for helping restore communication between nerve cells after a stroke.

“Basically, we are upsetting a lot of dogma that says the brain does not repair itself or recover, that there is no formation of new connections,” says study leader S. Thomas Carmichael, a professor of neurology and stroke specialist at the University of California at Los Angeles. “My lab is one of those that has showed that this is not true, and that has opened interesting molecular and cellular questions about what happens to regenerate the brain.”

Begging for an explanation

The research was rooted in some facts that did not jibe with the “no repair” dogma, Carmichael says. “Most strokes get a little better, and some get quite a bit better, in the weeks after the stroke. So our question is what events lead to this repair and recovery in the brain, and why they are limited.”

Several processes could explain these small recoveries, Carmichael says:

Brain cells are under both positive and negative controls; some chemicals make them more excitable, and others dampen their excitation. The study reported today was designed to test whether blocking a major inhibitory chemical would help neurons return to work after a stroke.

Just as two negatives make a positive, blocking an inhibitory chemical can stimulate a nerve cell.

The study concerned GABA, the major inhibitory compound in the brain. GABA released at a synapse, where neurons connect with each other, causes other neurons to briefly be less excitable. In the 1990s, an “extra-synaptic” receptor for the same compound, GABA, was found elsewhere on the nerve cell. “This is a whole separate group of GABA receptors that are on the cell body,” says Carmichael. “They don’t respond to GABA released into the synapse, but to GABA that spills over.”

Because these receptors are built differently, they can be blocked without affecting the synaptic GABA, says Carmichael.

During the experiment, Carmichael and colleagues used chemical or genetic mechanisms to block extra-synaptic GABA, and found that the mice recovered 30 to 50 percent of their motor coordination in various tests.

Neurons in the area around the injury started conversing once again, but only if they had been treated with the GABA inhibitor.

Courtesy S. Thomas Carmichael, UCLA

After a stroke, mice received three treatments. “Foot faults” measured their coordination; mice that got the experimental drug L655,708 were more coordinated than untreated mice.

Red: Stroke alone.

Blue: Stroke + GABA-inhibiting compound

Green: GABA-inhibiting compound (no stroke)

A promising drug?

Many drugs cannot enter the brain, but Carmichael says the oddly-named L655,708 can do so. And since it’s in early-stage human trials, it has already satisfied preliminary safety standards. More important, no other drug treatment has been able to put intact, but “stunned,” neurons back to work following a stroke, Carmichael says.

In essence, the treatment seems to “change the set point of neurons,” Carmichael says, making them more excitable — without affecting the synapse. “Inhibiting or blocking all inhibition of synaptic signaling would put you to sleep or give you a seizure, and neither is desirable after a stroke. The nice thing about this receptor is that it is involved in a completely different situation.”

“The research is both important and relevant,” commented Matthew B. Jensen, an assistant professor in the Comprehensive Stroke Program at the University of Wisconsin-Madison. “Post-stroke disability is a major public health problem, and we need to better understand the limitations for recovery of the nervous system after injury to be able to design effective treatments.”

“The study matters because it suggests a new target for treatments to improve stroke recovery,” Jensen added, although it is not completely clear that the drug acted solely in the area near the stroke, or also elsewhere in the nervous system.

The 30 to 50 percent improvement is “dramatic, an impressive recovery,” says Carmichael. Treatment for strokes focuses on restoring blocked blood flow, but “If you look at stroke literature, there are no drugs that promote recovery” of lost function.

But this is only one study, as Carmichael admits. “We have done this in one lab, and somebody has to replicate these findings.”

Once that happens, it should be time to test the drugs in stroke patients. Although mice are not people, “At that point, we will have done all we can with a non-human model.”

– David J. Tenenbaum