The failure of the adult central nervous system (CNS) to regenerate after injury is a major clinical problem, affecting some 200,000 people in the USA alone. Despite many years of study, progress toward a cure has been frustratingly slow, and the prospect of being able to promote significant regeneration of severed central axons remains a distant one. Yet the peripheral nervous system can regenerate, as can parts of the CNS of lower vertebrates, and even the mammalian CNS shows some regenerative ability in early life. What determines whether or not regeneration occurs?

One answer seems to be myelin; CNS myelin contains inhibitors that block the growth of axons in culture and may do the same in vivo. Some of the most encouraging results in this field have come from Martin Schwab and his colleagues at the University of Zurich, who for more than a decade have been studying the basis for this inhibitory effect. They previously generated a monoclonal antibody, IN-1, which blocks at least some of the inhibitory activity of CNS myelin. Treatment with IN-1 promotes regeneration of cut axons in the spinal cords of rodents, and this regeneration is accompanied by significant functional recovery of limb movements (see Nature 378 p 498).

It was tempting to attribute the functional recovery to the observed anatomical regeneration, but the results were never quite that clear-cut. For one thing, the amount of regeneration was very modest, typically no more than 5 or 10% of the original projection, and there was little evidence that the regenerated axons re-established their normal connections. The functional recovery on some tests seemed impressive in quantitative terms, but in no sense can these tests be considered a linear measure of functional regeneration. Most importantly, it was not possible to rule out the possibility that some, perhaps even most, of the recovery was due to compensatory plastic changes elsewhere rather than to the regeneration of damaged axons.

The paper on page 124 of this issue (see also page 87) will force a reevaluation of these findings, and of the field of spinal cord regeneration in general. Using more precise surgical and anatomical methods than were previously available, Schwab and his colleagues have now examined the anatomical and functional effects of the IN-1 antibody following a well defined lesion to the corticospinal tract (CST). They observe an apparently complete recovery on a range of functional tests, from climbing a rope to removing sticky tape from the forepaws. More importantly, they find evidence for extensive plastic changes at numerous sites in the brain and spinal cord that may account for this recovery.

In contrast to previous studies, the lesion is placed in the pyramid of the brainstem, where the CST is exposed and can be cut with minimal damage to other spinal fibers. CST fibers are only a small component of the spinal cord, and their role in movement control is relatively subtle. (For example, the lesioned rats can still climb a rope; they merely slip more frequently.) It may be the precision of the lesion that allows such extensive recovery compared to what has been reported previously.

The authors labeled CST axons on both the lesioned and unlesioned sides, and found extensive branching in both cases. Thus, the lesioned CST extends new branches from the intact section that lies proximal to the lesion site, while the unlesioned contralateral tract is somehow induced to give rise to new collaterals in the spinal cord, which cross the midline and appear to innervate the denervated contralateral gray matter. Any or all of these connections could explain the functional recovery. Moreover, because the authors only labeled the CST, it is entirely possible that other parts of the brain or spinal cord may also have undergone substantial anatomical remodeling. Determining which (if any) of these new connections are responsible for the functional recovery is likely to be a challenging task, to say the least.

Importantly, this remodeling is only seen in animals that are both lesioned and treated with IN-1 antibody. The implication is that the lesion induces some kind of sprouting tendency that is normally kept in check by whatever molecule(s) are blocked by the antibody. This raises a number of questions. What does the lesion do to axons that makes them sprout? What about the unlesioned axons that also put out new collaterals: do they undergo some intrinsic change that alters their growth properties, or are they simply responding to external cues, perhaps diffusible factors released from nearby denervated gray matter? And above all, what is the inhibitor itself and how does it work? What might be its role in normal animals?

Clearly, the target of the IN-1 antibody is likely to be a molecule of some importance. Schwab and colleagues have recently announced that a putative inhibitor has now been cloned (Soc. Neurosci. Abstr. 675.16, 1997), and publication of these data will be eagerly awaited. Among the key questions will be whether this molecule is required for the inhibitory activity of myelin, and whether it alone is sufficient to reconstitute such activity. If they have identified the right gene, the availability of the sequence should greatly accelerate progress in understanding the basis of the response to neuronal injury, and perhaps of normal plasticity in development and adulthood.

Whether it will also accelerate progress in spinal cord repair is less clear. The new findings suggest that the picture is not likely to be simple. It is by no means certain that blocking the target of IN-1 will facilitate substantial or clinically meaningful regeneration in other species, either of the CST or of other severed axons. It may, on the other hand, be a powerful way of inducing new neuronal growth, which might lead to a variety of clinical benefits; but that will be another story.