The self-healing highway

Wounds heal, but not severed nerve cords. This dogma no longer applies, now that neuroscientists have discovered and released the molecular brakes of nerve regeneration. A highway that links up brain and body - is how Dr. Ana Martin-Villalba (35), neuroscientist at the German Cancer Research Center, describes the spinal cord. It's a fitting image, because, until recently, neurobiologists believed that just as a breach in a highway does not sometime mend on its own, it was just as unlikely for a spinal cord to be able to regenerate itself following an injury. Three years ago, however, Martin-Villalba managed to get the ends of the highway to grow towards each other as if by magic, albeit only in a lab mouse: the severed spinal cord nerves of laboratory mice grew together so well that the paraplegic mice were able to walk and even swim again.

The trick used by the Spanish-born scientist was to stop a process that actually performs valuable work in the event of an injury. Because so much "debris" lies around after a spinal cord injury: broken cells, scar tissue, and loads of inhibitors and signalling cues that "clear up" the accident site by making the displaced cells commit suicide. It would seem that CD95-L is a particularly hard-working member of the clean-up team. The signal molecule also causes the nerve cells to die and so prevents regeneration. As soon as CD95-L contacts the cell surface, the internal DNA starts to dissolve and the cell dies. Unfortunately, this also applies to nerve cells.

It seemed only logical to hypothesise that intercepting the CD95-L could have a positive effect on the regenerative ability of the nerve cells. And after four weeks of treatment with an antibody against the CD95 ligands, Martin-Villalba's mice did indeed start walking again. A eureka moment that only few researchers get to experience. "But such moments are always short-lived, because the real work starts from then," she says. Meanwhile, Martin-Villalba is also thinking well beyond CD95-L. Because if paraplegic patients are to be healed, then it's not enough just to inhibit this cue, that's for sure: Chondroitinase is needed, for example, to make the scar tissue permeable again, so that the nerve cells can grow through the tissue. Nogo/Ng-R66 blocks the inhibitors released by the destroyed nerve fibres. And nanomaterials could create a kind of basis for the regenerating nerve cell to attach itself to. And then there are agents that regulate the inflammatory reaction or accelerate the regenerative ability of nerve cells, such as cAMP or ROK inhibitors. Eventually, this could mean that patients get a kind of cocktail of these substances, says Martin-Villalba.

"However, we first have to learn much more about the pathophysiology of spinal cord injuries and about how the various components interact." Martin-Villalba is aware of how closely her work is being followed by paraplegic, stroke or brain tumour patients. And she repeatedly gets letters asking for help. "That's a very difficult part of my work, because these questions repeatedly make it clear to me how far away we still are from actually being able to help all these patients," sighs Martin-Villalba. "I truly wish that I could open up options for a treatment. But right now, we are still at the level of basic research." Nevertheless, the medical scientist advises Apogenix GmbH, a biotech company that plans to carry forward the CD95 research through to therapeutic application. "I hope that we manage to achieve this one day..."