Contributions of the Bunge laboratory.

“… We may thus infer from what has been said that, in man as in laboratory animals, the regenerative act commences, and may even attain certain strength, on condition that the traumatic commotion be sufficient to stir the axons out of their lethargy…. As is known, this tendency to restoration is frustrated by two negative conditions (1) the lack of substances able to sustain and invigorate the indolent and scanty growth of the sprouts; and (2) the absence in the paths or systems of interrupted nerve fibres of catalytic agents capable of attracting and directing the axonic current to its destination. … If experimental neurology is someday to supply artificially the deficiencies in question, it must accomplish these two objects: it must give to the sprouts, by means of adequate alimentation, a vigorous capacity for growth; and place in front of the disoriented nerve cones … specific orienting substances. (Cajal, 1928)” Ramon y Cajal recognized early on that regenerative failure was a multifaceted problem and that, because of this, a combinatorial approach would be needed to stimulate regeneration or sprouting to a purposeful end. Some of the conditions essential for promoting regeneration, he thought, would be “almost impossible to satisfy” but the situation was not hopeless. With these thoughts, Cajal introduced and reviewed the classic experiments of his student Francisco Tello, who first documented the successful use of Schwann cell-laden, pre-degenerated, peripheral nerve grafts to stimulate, at least transiently, axonal regeneration of fully adult central nervous system (CNS) axons (1). In this lovely review of more than a decade of her work, and in tribute to the vision of the late Richard Bunge, who, with Mary, focused much of his scientific career studying the cell of Schwann, Mary Bunge has summarized the results of a series of laborious and scrupulously orchestrated experiments that have focused attention on this powerful regeneration-promoting cell (2). For all the reasons described in this review, it is clearly one of Nature's most outstanding substrates for building a regeneration bridge across a lesion in the spinal cord. With increasing emphasis in recent years on the use of stem/progenitor cells to ameliorate the functional losses that ensue after cord injury, it is important to keep in mind that autologous transplantation of adult Schwann cells has been made clinically feasible by the Bunge's, due to their painstaking and eventually successful efforts to perfect techniques for expanding adult human Schwann cells to very large numbers. What is perhaps most remarkable about the experiments from the Bunge laboratory is that much of the work has utilized a truly complete transection model, the most difficult of all to employ for studies of spinal cord injury. Importantly, however, the complete transection paradigm essentially assures that whatever recovery is gained caudal to the lesion cannot be mediated via axons that had been spared by the lesion. The seminal studies of Aguayo (3) and followed later by those of the Bunge's, showed that adult CNS axons could regrow for remarkably long distances within a PNS environment, but were largely stymied in their attempt to regain entrance into the CNS. Since then, in a meticulously controlled series of experiments over the years, Dr. Bunge and her colleagues have systematically attempted to alter a variety of intrinsic as well as extrinsic factors that actively block regeneration out of the bridge. I think it fair to say that the papers by Fouad et al (4) and Pearse et al (5), 2004 (coupled with a recent paper from the Houle and Silver laboratories using a hemisection model) (6) are the present culmination of this effort. Together, they have documented the most successful, functionally beneficial regeneration across spinal cord lesions with the use of Schwann cell bridges to date. While the amount of regeneration and recovery is still not optimized, the Bunge's have gotten us on our way. The question remains whether we have at hand so fundamental an understanding of the many contributors to regeneration failure that we are now in a position to devise strategies, with the help of Schwann cells, to allow us to move more rapidly toward a clinically efficacious therapy. The use of combinatorial tactics to promote functional regeneration has now become a major theme of modern regeneration biologists due in large part to the work of Mary Bunge. After reading this article, which also reviews work with the more clinically relevant, contusive injury model, I think that we are, indeed, entering an era where strategies for providing functional benefit in animal models of spinal cord injury are sufficiently robust that there should be optimism for translational success.