As reported by the New Haven Register, April 24, 2005.

‘Cure’ No Longer Wrong Word in Paralysis Research

By Abram Katz

John Bollinger doesn’t expect to rise from his wheelchair, but he would like to regain control of his right hand.

Controlling those five fingers could make a huge difference.

Holding a pen, using a telephone, dressing, shaving, picking up a paperclip — that would be a cure.

Until recently, Dr. Stephen G. Waxman, director of the Yale University-affiliated Center for Neuroscience and Regeneration Research, refused to use the c-word.

Repairing severed spinal cords, treating multiple sclerosis or relieving the intense pain that lingers after an amputation were far too distant goals.

"Cure" was a false promise.

Now, restoring certain physical functions and mending torn, severed or diseased nerves is almost in reach.

But a gulf still separates the rosy public perception of nerve restoration and the vast complexity of even returning Bollinger’s hand.

Research on rats is intriguing, but re-connecting a 2-inch rat spinal cord is not the same as re-animating a 3-foot human cord, neurologists said.

Wildly optimistic tales of Chinese doctors repairing human spinal cords with injections of cells are impossible to verify.

Even many rigorous studies around the world cannot be reproduced.

Yet the center’s research on the way nerves die, remission in multiple sclerosis and the role of sodium channels in paralysis and pain hold enough promise to change Waxman’s carefully chosen vocabulary.

"For years I felt I couldn’t use the word ‘cure,’" Waxman told rapt members of the Paralyzed Veterans of America (PVA), who sat gridlocked in a small meeting room at the Veterans Affairs medical center in West Haven.

"The aggregation of research makes a cure seem possible, feasible," Waxman said after briefing the group on the center’s latest research.

"Compared to 15 years ago, the science has undergone a sea change.

But it is slow," Waxman said.

The center is a one-story brick building tucked behind the VA.

It’s a collaboration between the PVA, the United Spinal Association and Yale.

The PVA visited the center in West Haven last week to give the center and Yale a quarter of a million dollars.

Bollinger, 59, of Alexandria, Va., is deputy executive director of the Paralyzed Veterans of America. He was in the Navy and stationed in Panama in December 1969.

He broke his neck in a diving accident.

Bollinger said he thinks nerve repair and restoration will advance in increments.

"Little improvements that seem minimal could make a big difference. They could make someone independent," he said.

Ken Medeiros of Taunton, Mass., is president of the New England Chapter of the PVA.

He has no visions of walking again, either.

"When Waxman uses ‘cure,’ it’s in the future. It’s terrific," said Medeiros, 63.

He was in the 101st Airborne Division during the height of the Cuban missile crisis in 1962.

"We were all on ‘red alert.’ We were training in case we had to go to Cuba," he said.

Medeiros was injured on these maneuvers and has not walked since.

"There was no optimism way back then. A cure was considered science fiction. This is very encouraging. I believe Dr. Waxman.

It’s slow but progressing. We’re taking baby steps toward the finish line."

American physician Silas Weir Mitchell started the study of phantom limb pain in Civil War veterans.

Soldiers continue to feel the same neuropathic blizzard of pain impulses.

"The people we send overseas today are not that different than the soldiers in the Civil War," Waxman said.

In fact, soldiers and Marines wearing body armor in Iraq and Afghanistan are losing more limbs but experiencing fewer spinal injuries, veterans said.

And now there’s real hope for neuropathic pain.

Waxman said research at the center has shown that when nerves are severed, genes for normal sodium channels become silent.

The "wrong" kind of sodium channels, Type 3, appear on injured nerves. It is believed that the Type 3 channels are somehow stimulated to fire like a machine gun when they should be quiet.

The result is intense and intractable pain.

Waxman said scientists at the center created an anti-sense version of the Type 3 gene. It’s the genetic reverse of the gene, and when the two combine, they lock and the gene is deactivated.

Pain disappeared.

This therapy is not available for humans, but drugs that can accomplish the same mission are likely in the near future, Waxman said.

There’s no way to protect nerves when a limb is lost, but there may be a way to preserve cords injured in car crashes and other accidents, Waxman said.

"Damaged cells don’t die for days," he said.

Researchers at the center have mapped the nerve cell death cascade. Blocking this process could prevent damage, he said.

The center is preparing to study a candidate drug, phenytoin sodium (Dilantin), on people with multiple sclerosis to see if it can protect nerve cells from further damage.

A greater challenge is how to replace lost insulation around the long axons of nerve cells.

A lipid-rich protein called myelin normally protects and insulates axons.

In multiple sclerosis, the body attacks its own myelin.

Waxman found that when the protective protein is stripped away, the normal sodium channels are replaced by an unhelpful kind.

He compares channels to batteries. C-cells in a D-cell flashlight won’t work. Neither do the wrong sodium channels.

If scientists could figure out why the useless sodium channels arise, drugs or other therapies might be able to block them or restore the correct channels.

The center has specially engineered rats with no myelin.

Stem cells from an adult rat’s marrow were injected into the injured rat.

The cells homed in on the damaged areas and differentiated myelin. The experiment even worked with adult human marrow stem cells.

Jeffrey D. Kocsis, associate director of the center, said, "We have ‘cured’ severe spinal cord injury in rats with stem cells."

Kocsis said that unfortunately, rat therapy does not translate to humans.

Besides, the roadblocks to repairing decades-old spinal cord injuries like Bollinger’s and Medeiros’ are enormous, he said.

Stem-cell experiments with rat neurons should instead be considered basic research intended to shed light on the biology of nerves and nerve damage, he said.

Richard Mains, chairman of neuroscience at the University of Connecticut Medical Center in Farmington, said a basic problem common to cord injuries is broken circuitry.

The normal nerve travels down the spine to its target receptor, and the sensory nerve from the muscle to the brain completes the circuit.

If any of these parts are compromised, the nerve will not work.

This is why although nerve growth factor proteins can attract expanding nerves, the exercise does little good, he said.

Neither would simply stimulating nerve growth.

"Even if the axons are preserved, maybe the target is a problem or the circuit is a problem because it doesn’t form a loop," Mains said.

The higher up the spine the cord is damaged, the easier it should be to restore function, Mains said.

That’s promising for Bollinger’s dexterity.

"Definitions of a ‘cure’ vary a lot," Waxman said. "Minimal repair, relief from pain. Now we know how axons die, and we’re almost ready to start a clinical study."

Perhaps soon, emergency medical technicians will be equipped with drugs to block neuronal death.

The drugs will be administered on the way from the accident scene to the hospital. A potentially paralyzing injury would be averted.

Ultimately, scientists must determine how cells differentiate and develop, Waxman said.

Meanwhile, "we only need to understand enough."