Science Editor

The brain is capable of impressive plasticity in many respects. But there is an exception: Connections in the brain and spinal cord - collectively known as the central nervous system - do not regrow after an injury.

"There are two reasons why neurons fail to regenerate in the CNS," Marc Tessier-Lavigne told BioWorld Today. First, the neurons themselves - which can migrate and form connections over impressive distances during early development - become intrinsically less able to grow as they mature.

Second, the environment is hostile to such regrowth after an injury. Nervous system support cells form what is known as a "glial scar" at the site of an injury, secreting inhibitory proteins and preventing neurons from crossing the scar and re-connecting with their former targets.

Tessier-Lavigne is executive vice president for research and drug discovery at South San Francisco-based Genentech Inc. and senior author on one of two papers in the Nov. 7, 2008, issue of Science that addressed those two problems, respectively.

The paper by Tessier-Lavigne and his group, which included co-authors from Harvard and Stanford Universities as well as from Genentech, reported on a new receptor that prevents regrowth by sensing and responding to signals from the glial scar: the Pirb-1 receptor.

The best-known actors in the glial scar are three proteins (Nogo, MAG and OMGp), which are secreted by myelin, bind to the Nogo receptor and inhibit growth.

But in animal studies, knocking out the Nogo receptor did not do all that much to promote the growth of axons, suggesting that there must be an additional receptor that binds the same proteins.

Tessier-Lavigne and his team identified that receptor through screening, and tested the effect of blocking it in cell culture. They found that when they either knocked out the receptor or blocked it with antibodies, cultured neurons were able to grow even in the presence of inhibitory proteins. Blocking both Pirb-1 and Nogo further increased their growth.

All the work reported in Science is in vitro, But Tessier-Lavigne said that in vivo work is in progress. The authors are interested in creating double knockouts for Pirb-1 and Nogo receptors, and seeing whether there is any evidence for regeneration after injury in such animals.

A second paper in the same issue of Science, this one by researchers from Harvard Medical School, showed a potential way to address the complementary issue, namely, that neurons become intrinsically less able to regenerate as they age. In the paper, the authors showed that axons of the optic tract - which is part of the central nervous system and normally does not regrow after injury - were able to do so when the scientists used a viral vector to conditionally knock out the tumor suppressor PTEN in animals. That intervention up-regulated the mTOR pathway, prevented cell death and led to axon outgrowth.

PTEN is well known to drug developers, but generally for the opposite reason. Its deletion appears to be responsible for a number of different cancers.

Asked whether the idea of manipulating a tumor suppressor might seem like a somewhat risky prospect, Tessier-Lavigne (who is not a co-author on the second paper) acknowledged that "it's ideal to target specifically the mechanism you are interested in."

But, he added, the important point of the paper by the Harvard scientists is the identification of a pathway that can be manipulated to induce axonal growth even under unfavorable conditions. As such, the work presents "an opportunity to look for targets within that pathway," downstream of PTEN itself, that could allow for such specific targeting.

The two papers showed work on different axonal tracts: visual neurons in one case, and cerebellar and spinal neurons on the other. The main therapeutic use for axonal regrowth, of course, is in yet another neural tract: the spinal cord. Different neural tracts are known to respond differently to attempts at getting them to regrow, and so it is not clear how general the approaches described in each of the papers are. Tessier-Lavigne said that at this point, "it is not known why different tracts respond differently" to regeneration-inducing stimuli.

But, he added, even if an approach that works well on one neural pathway fares less well in another, incremental advances also are worth pursuing therapeutically. "The good news is that even a small degree of regeneration may be able to reconnect local circuits, and give some degree of functional improvement," he said.

For a paraplegic, for example, arm control would be useful even if fine motor control of the fingers cannot be achieved: "even gaining some measure of movement . . . is going to be valuable."

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