May 15, 2012

Collaborations Guide UT’s Guru of Nerve Repair

George Bittner is a professor at The University of Texas at Austin who developed a procedure curing paralysis in rats. Bittner’s research group is moving forward with clinical trials in humans giving hope to people affected by paralysis. Photo by Fanny Trang.

By Jordan Humphreys
For Reporting Texas

After 43 years in the hunt, George Bittner, professor of neurobiology at the University of Texas at Austin, believes he’s on the verge of a major breakthrough in nerve repair that could potentially cure paralysis in humans.

For the moment, however, Bittner’s focus is exclusively on rats. His lab has developed a procedure combining common chemicals, found in laxatives and eye drops, and microsurgical techniques to reconnect severed sciatic nerves in rodents. Sciatic nerves control motion and feeling in the legs, and Bittner’s technique makes reconnection possible by keeping nerve endings from sealing themselves.

“It worked like a charm,” said Bittner of the first trial in fall 2011. “The first animals were walking in a week.”

But even a sizeable leap in rats is not necessarily an advance for humankind. While nerve structures in the two species are similar, many steps separate animal trials from the more stringent procedures the federal government requires to clear breakthroughs in the lower mammals for human use.

Still, some scientists think there’s reason for optimism. “This could make a big difference for people with … injuries where current repair strategies often lead to poor outcomes,” said Wesley Thayer, a plastic surgery professor at the Vanderbilt School of Medicine, who is participating in the study.

As Bittner sees it, collaboration is the key to more progress. His lab at UT has teamed up with researchers at Harvard and Vanderbilt medical schools and is working with the National Institutes of Health and the Food and Drug Administration to prepare for clinical trials.

In developing the technique for nerve repair, Bittner also sought advice from surgeons across the country, professors across the university and his own research assistants, including undergraduates.

Todd Krause, a student who worked with Bittner as an undergraduate and throughout his Ph.D. study from 1986 to 1993, said the lab’s atmosphere of collaboration at all levels helped researchers look for outside-the-box answers.

“George was big about ‘gee whiz’ moments: He asked questions and explained things that people normally wouldn’t,” said Krause, now a biotechnology intellectual property lawyer. “He’d ask: ‘Is it possible, and can I test it?’ and that taking on big issues and not feeling timid created an environment of collaboration to be receptive to good ideas.”

Bittner’s current technique involves three stages. The first keeps the ends of severed nerves open so they can be reconnected, the second pulls each end of the cut nerve toward the other using various chemicals that prompt their joining, and the third ties the nerves together surgically to keep them from breaking when the animal moves.

Surgeons have to move fast. Once nerve cells, called axons, are cut, they immediately seal themselves off at both ends (in humans, as quickly as one day after the injury) cutting off access to feeling and nerve impulses south of the cut. Once these seals are formed, prospects for reconnecting the nerve are slim.

Bittner struggled with this challenge until 2010, when Francisco Gonzalez-Lima, a psychology professor and fellow researcher at UT, insisted he try methylene blue, a long-used dye, which recently showed its value for keeping cells open.

“Methylene blue has been able to prevent neurodegeneration,” Gonzalez-Lima said. “This collaboration led to a breakthrough in that the animals treated with methylene blue recovered faster and better.”

Once nerve cells are opened, the procedure calls for applying polyethylene glycol (PEG), a chemical that causes cells to drift together, aligning each end of the severed axon. A trip to the movies in 1980, to see “The Empire Strikes Back,” inspired Bittner to use PEG for the first time in an animal thanks to a scene in which Luke Skywalker’s hand is reattached after a light saber duel.

“In the 15-minute drive home, I started to think: “You know, that’s what I’ve been wanting to do. If you take the distal and proximal halves [the dead stump and live end], it’d be an intact cell,” said Bittner, recalling how, the next day, he used PEG on a crayfish for the first time.

Bittner’s team perfected his current technique in 2011 after its research on the PEG-methylene-blue combination attracted the attention of surgeons nationwide. Hand surgeons suggested the lab try holding nerves together with microsutures, super-precise stitches used for small tendons.

“Dr. Cameron Keating [a plastic surgery researcher from Massachusetts General Hospital at Harvard Medical School] came down to combine the methylene blue procedure with his microsutures,” Bittner said.

The results were dramatic. Animals that were operated on experienced 80 percent nerve regeneration compared with untreated rats, which registered under 15 percent. It was the trifecta of first PEG, then methylene blue and last microsutures that had success in animals, with little success from each component on its own.

“Without the series, you don’t get real success,” Bittner said.

The road to possible success in humans remains a demanding one. Despite its potential to cure paralysis, the FDA has to approve the procedure and specific chemicals for a trial, and then the researchers can work with NIH to move forward with clinical trials.

The study’s researchers are already seeing how far they can translate results. Bittner said Thayer is working on double fusions, reconnecting nerves at both ends, which may one day lead to a successful procedure for nerve transplants.

“It leads us to hope for the day that we can repair nerve damage in humans,” Bittner said.