In Memoriam: Richard Paul Bunge

The neuroscience community has lost a pioneer, a mentor, and a generous colleague with the death of Dr. Richard Paul Bunge on September 10, 1996, at the age of sixty four. A man of great integrity and modesty, Dick had a profound influence on our field. For him, science was its own reward; he did not seek to personalize his achievements.Dick was a product of the heartland, the son of a small town South Dakotan minister. He attended college and medical school at the University of Wisconsin. While still a medical student working part-time in a research laboratory to defray his tuition, he published his first paper, and thereafter, he embraced a career in basic science while retaining an eye for its clinical potential. He married a young graduate student, Mary Elizabeth Bartlett, who was to become his close scientific collaborator. Many of their major findings grew out of this lifelong partnership. For legions of students and junior associates, the Bunges were role models, a professional couple who enjoyed highly successful research careers and yet maintained a vibrant family life with their two sons.In Madison, they began by investigating the paralysis that results from repetitive, partial exchanges of the cerebrospinal fluid in the cat spinal cord, a procedure they showed leads to substantial demyelination (Bunge et al. 1960xElectron microscopic study of demyelination in an experimentally induced lesion in adult cat spinal cord. Bunge, R.P., Bunge, M.B., and Ris, H. J. Biophys. Biochem. Cytol. 1960; 7: 685–696Crossref | PubMedSee all ReferencesBunge et al. 1960). Using this paradigm in a pioneering electron microscopic study, the Bunges demonstrated for the first time remyelination in the vertebrate CNS (Bunge et al. 1961xUltrastructural study of remyelination in an experimental lesion in adult cat spinal cord. Bunge, M.B., Bunge, R.P., and Ris, H. J. Biophys. Biochem. Cytol. 1961; 10: 67–94Crossref | PubMedSee all ReferencesBunge et al. 1961). These early studies also provided compelling evidence that the central myelin sheath is formed by the spiral wrapping of a glial process around an axon (see Figure 1Figure 1), similar to what had been proposed for the PNS and not by compaction of flattened membrane stacks secreted by many glial cells as had been suggested by others. In a seminal study, they next demonstrated direct continuity between the oligodendrocyte and the myelin sheath, thereby definitively establishing the oligodendrocyte as the myelinating cell in the CNS (Bunge et al. 1962xElectron microscopic demonstration of connections between glia and myelin sheaths in the developing mammalian central nervous system. Bunge, M.B., Bunge, R.P., and Pappas, G.D. J. Cell Biol. 1962; 12: 448–453Crossref | PubMedSee all ReferencesBunge et al. 1962).Figure 1Myelination in the CNS Occurs by Spiral Wrapping of an Oligodendrocyte Process around an AxonThe cut away shows separate lamellae of the myelin sheath and the paranodal loops. Reprinted, with permission, from Bunge et al. 1961xUltrastructural study of remyelination in an experimental lesion in adult cat spinal cord. Bunge, M.B., Bunge, R.P., and Ris, H. J. Biophys. Biochem. Cytol. 1961; 10: 67–94Crossref | PubMedSee all ReferencesBunge et al. 1961.View Large Image | View Hi-Res Image | Download PowerPoint SlideFrom Madison, they moved to the Department of Anatomy at the College of Physicians and Surgeons to work with Dr. Margaret Murray, who was developing tissue culture methods to study myelination and synaptogenesis in vitro. To obtain myelination in culture at that time required patience, fortitude, and good luck. Sensory ganglia were maintained in a complex medium containing human placental serum and chick embryo extract and kept in glass chambers sealed with wax. These organotypic cultures were prized for the complexity of structure that could be recapitulated in vitro.At Columbia and later at Washington University in St. Louis, Dick refined and streamlined the myelinating culture system to the highly reliable in vitro system that is in widespread use today (reviewed byKleitman et al. 1991xSee all ReferencesKleitman et al. 1991). These cultures have been an important source of insight into the mechanisms of myelination and of neuronal–glial interactions. Working with Dr. Patrick Wood, Dick established that the axon was mitogenic for Schwann cells and oligodendrocytes (9xEvidence that sensory axons are mitogenic for Schwann cells. Wood, P.M. and Bunge, R.P. Nature. 1975; 256: 662–664Crossref | PubMed | Scopus (224)See all References, 10xEvidence that axons are mitogenic for oligodendrocytes isolated from adult animals. Wood, P.M. and Bunge, R.P. Nature. 1986; 320: 756–758Crossref | PubMed | Scopus (69)See all References), providing the first example of the biological activity we now recognize as the neuregulin family of growth factors. The Bunges demonstrated (Bunge et al. 1989xMovements of the Schwann cell nucleus implicate progression of the inner (axon-related) Schwann cell process during myelination. Bunge, R.P., Bunge, M.B., and Bates, M. J. Cell Biol. 1989; 109: 273–284Crossref | PubMedSee all ReferencesBunge et al. 1989) that the myelin sheath develops by advancement of the inner spiral around the axon (see Figure 2Figure 2) rather than via circumnavigation of the Schwann cell body around the axon, as previously suggested. They recognized the importance of the Schwann cell basal lamina for normal myelination (Bunge et al. 1986xLinkage between axonal ensheathment and basal lamina production by Schwann cells. Bunge, R.P., Bunge, M.B., and Eldridge, C.F. Annu. Rev. Neurosci. 1986; 9: 305–328Crossref | PubMedSee all ReferencesBunge et al. 1986) and began studies on the functional role in myelination of several cell adhesion molecules. Dick appreciated that Schwann cells are an important source of trophic factors (Varon and Bunge 1978xTrophic mechanisms in the peripheral nervous system. Varon, S.S. and Bunge, R.P. Annu. Rev. Neurosci. 1978; 1: 327–361Crossref | PubMedSee all ReferencesVaron and Bunge 1978) and this notion, together with the recognized capacity of the Schwann cell to promote regeneration, lead him to propose early on the possibility of transplanting glial cells into the central nervous system to treat neurologic disorders (Bunge 1975xSee all ReferencesBunge 1975).Figure 2In the PNS, the Myelin Sheath Forms by Advancement of the Inner Turn of the Schwann Cell around an AxonReprinted, with permission, from Bunge et al. 1989xMovements of the Schwann cell nucleus implicate progression of the inner (axon-related) Schwann cell process during myelination. Bunge, R.P., Bunge, M.B., and Bates, M. J. Cell Biol. 1989; 109: 273–284Crossref | PubMedSee all ReferencesBunge et al. 1989.View Large Image | View Hi-Res Image | Download PowerPoint SlideHe became the Scientific Director of the Miami Project to Cure Paralysis in 1989 and thereafter devoted a great deal of his energies toward realizing the therapeutic potential of Schwann cells. Dick's appointment expanded and brought new vigor and respect to the scientific program of the Miami Project, simultaneously increasing national attention to the formidable problem of how to repair the injured nervous system. With characteristic zeal, reflecting a new focus on spinal cord injury, Dick refined our understanding of the response of the injured human spinal cord, combining MRI imaging with careful histopathology.In all of his work, Dick made astute inferences about biological phenomena based on careful and direct observation, always beautifully documented in his papers. He brought an enthusiasm and a generous spirit to his studies that attracted long-standing collaborations and inspired his students, many of whom continue to work in research areas he did much to define. As a mentor, Dick was patient and supportive, often spending more time with those who were struggling the most. For his students, the Bunge lab functioned as an extended family. It has struck many of us who have visited the Miami Project how successfully that spirit was reestablished there after the move from St. Louis.Dick was a gifted lecturer who was able to convey a sense of wonder at the beauty of biology. He was a towering physical presence at scientific conferences to which he brought a great breadth of knowledge and delivered frequent insights with wit and a twinkle in his eye.The last 20 months of his life, Dick displayed remarkable courage and dignity despite prolonged and debilitating treatments for esophageal cancer. Two weeks before he died, he shepherded a PhD student through his thesis defense; that was the last day he was able to come to work. Until the end, he retained his characteristic good humor and optimism and continued to be excited by science. In remembering Dick, we celebrate a life lived well and with great purpose.