Biography of Pietro De Camilli BIOGRAPHY

uring synaptic transmission, University, was a sort of ‘‘Italian out- neurotransmitter-containing post for the scientific school of George vesicles fuse with the plasma Palade,’’ De Camilli said. He considers D membrane, releasing neuro- Palade ‘‘my scientific grandfather, the transmitters into the synaptic space by mentor of my mentor [Meldolesi], and, exocytosis. In the subsequent seconds, really, he was my major inspiration in vesicle membranes are reinternalized cell biology.’’ With Meldolesi, De Cam- and reused for the next generation of illi studied mechanisms of secretion in synaptic vesicles. Over the last 25 years, exocrine and endocrine cells, focusing Pietro De Camilli has studied the mo- on how secretory vesicles fuse with the lecular mechanisms involved in this in- plasma membrane. De Camilli used tricate cycle of membrane traffic and freeze-fracture electron microscopy to has identified and characterized numer- visualize the distribution of membrane ous proteins that participate in the pro- proteins in exocrine glands, and he pro- cess. Trained as an M.D., he has also vided the first demonstration of physical made significant contributions toward differences between apical and basolat- understanding human diseases of the eral membranes in polarized epithelial nervous system that involve autoimmu- cells (2, 3). nity against synaptic proteins. Because After his training with Meldolesi, De the synaptic vesicle is a powerful model Camilli wanted to investigate how secre- organelle for studying fundamental Pietro De Camilli tion is regulated (4) and chose to do mechanisms in membrane–cytoskeletal postdoctoral work at Yale with Paul interactions, membrane fusion, and Greengard, who later won the 2000 No- membrane budding, De Camilli’s discov- said De Camilli. After obtaining a de- bel Prize for Physiology or Medicine. eries are relevant to secretory and endo- gree in classical studies from the Ly- Greengard was pioneering studies on cytic mechanisms in many fields beyond ceum Manzoni in Milan in 1966, De the role of second messengers and pro- neurotransmission. Camilli enrolled in medical school with tein phosphorylation systems in the reg- De Camilli, a professor in the Depart- the clear determination to be a scientist. ulation of the nervous system, including ment of Cell Biology at the Yale Uni- Because there were no Ph.D. programs the regulation of neurosecretion. At the versity School of Medicine (New Haven, in Italy at the time, he thought that the time, neurobiologists saw ion fluxes and CT), has received numerous honors and best path for pursuing a career in bio- electrical currents as the main mecha- awards. In 1987, De Camilli was elected logical research was through medical nisms underlying neuronal signaling. In to the European Molecular Biology Or- school. However, De Camilli had diverse contrast, ‘‘Paul was looking at what goes ganization and was appointed as a interests in science extending beyond Howard Hughes Medical Institute Inves- medicine, which he recognized before tigator in 1992. In 1997, he was the entering medical school. ‘‘I realized that The characterization Keith Porter Lecturer for the American I would sacrifice breadth, because I Society for Cell Biology. De Camilli was would learn only about one organism of synapsin helped elected to the National Academy of Sci- [the human], but I felt like I would ences and to the American Academy of learn about this organism in every possi- launch a new field of Arts and Sciences in 2001. In 2003, he was named Eugene Higgins Professor of ble dimension, from molecule to mind,’’ study devoted to the Cell Biology at Yale. De Camilli be- he said. In 1972, De Camilli earned his lieves that one of his most important M.D. degree, magna cum laude, from molecular dissection of contributions has been to demonstrate the University of Milan. He then ob- the crucial role of protein–lipid interac- tained a postgraduate degree in medical the synaptic vesicle. tions and phosphoinositide metabolism endocrinology from the University of in the control of membrane traffic at Pavia in 1975. the synapse; he reviews this topic in his An early mentor was Jacopo Mel- dolesi at the University of Milan in the on inside the cytosol and was discover- Inaugural Article, published in this issue ing a whole new layer of information of PNAS (1). Department of Medical Pharmacology and the Consiglio Nazionale delle processing. The field was new and fasci- The Path from Medicine to Basic Science Ricerche (CNR) Center of Cytopharma- nating,’’ De Camilli said. ‘‘It was won- derful for me to step into this new De Camilli grew up in northern Italy, cology. ‘‘He attracted me with his over- world with the fresh eyes of a cell where his interest in science was nur- whelming enthusiasm,’’ De Camilli said. biologist.’’ tured by his surroundings. ‘‘During the Meldolesi had recently returned from Soon after beginning his work with summers in my native village of Cittiglio The Rockefeller University (New York) Greengard, De Camilli was recruited by [now Brenta] near Lake Maggiore, I after working with Jim Jamieson and Palade to be an assistant professor at would spend a lot of time with farmers, George Palade, the 1974 Nobel Laure- and this is what really attracted me to ate for Physiology or Medicine. The the observation of nature. I was very CNR Center of Cytopharmacology at This is a Biography of a recently elected member of the

interested in botanics and gardening. Milan, whose faculty included Francesco National Academy of Sciences to accompany the member’s CELL BIOLOGY Eventually, my interest in medicine Clementi, Bruno Ceccarelli, and Nica Inaugural Article on page 8262. stemmed out of my interest in nature,’’ Borgese, all trainees of The Rockefeller © 2004 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0403132101 PNAS ͉ June 1, 2004 ͉ vol. 101 ͉ no. 22 ͉ 8259–8261 Downloaded by guest on September 29, 2021 22) and the critical physiological impor- tance of phosphoinositide metabolism in the regulation of the vesicle cycle (23– 25). ‘‘I think we helped, in the last 10 years or so, to bring to center stage the critical role of lipids in membrane traf- fic,’’ De Camilli said. Scientific and Medical Interfaces Because the exo-endocytic recycling of synaptic vesicles represents a specialized form of the vesicle recycling that occurs at all cell surfaces, De Camilli’s studies on presynaptic function have contrib- uted to understanding the basic science of membrane traffic. ‘‘My work is at the interface of neurobiology and cell biol- ogy. I work in neurobiology, but with a keen interest in understanding cell bio- logical principles. Many of the processes and molecular interactions that we have studied in synapses apply to all cells,’’ De Camilli said. Electron microscope image of a synapse in the cerebellar cortex. The presynaptic compartment is densely Because of his medical background, populated by small, synaptic vesicles that store and secrete neurotransmitters. De Camilli has always searched for con- nections between his cell biology studies and clinical medicine. Knowing that the Yale University School of Medicine United States permanently. He became neurons and endocrine cells share simi- in the Section of Cell Biology. ‘‘I was associate professor in the Department lar secretory mechanisms, De Camilli vacillating, because I wanted to go back of Cell Biology and the Section of and his students Franco Folli and to Europe, but I decided to accept,’’ he Molecular Neurobiology at the Yale Michele Solimena hypothesized that au- said. While working with Greengard and School of Medicine in 1988 and was toimmunity directed against endocrine his postdoctoral fellow Wieland Huttner promoted to full professor in 1992. cells may also produce autoimmune at Yale, De Camilli demonstrated that From 1997 to 2000, De Camilli served neurological symptoms. To investigate the protein synapsin is selectively associ- as Chairman of the Yale Department of ated with the surface of cytoplasmic Cell Biology. vesicles in all nerve terminals. These ‘‘I think we helped to studies yielded a triplet of publications The Ins and Outs of Synaptic Vesicles in the Journal of Cell Biology (5–7). The Beginning with his work with Greengard bring to center stage characterization of synapsin helped on synapsin, De Camilli has spent his launch a new field of study devoted to career investigating the molecular inter- the critical role of lipids the molecular dissection of the synaptic actions that direct the synaptic vesicle vesicle. ‘‘At the time, the synaptic vesicle cycle. Working independently and in in membrane traffic.’’ was simply known as an organelle. It collaboration with Reinhard Jahn was important to elucidate each of its (Yale University School of Medicine, components, and synapsin was one of New Haven, CT) and Thomas Su¨dhof this hypothesis, De Camilli and his the first components to be identified,’’ (University of Texas Southwestern Med- students tested the serum of a patient he said. ical Center, Dallas), he contributed to suffering from both insulin-dependent Two years after moving to Yale, De the first molecular and functional char- diabetes mellitus and a rare neurological Camilli decided to return to Italy. ‘‘I felt acterization of synaptic vesicles (8–11). condition of unknown pathogenesis, very committed to go back to Europe, De Camilli then shifted his focus to stiff-man syndrome. The researchers dis- and I did.’’ He returned to the site of mechanisms of synaptic vesicle reforma- covered that the patient had a high titer his original training, the University of tion after exocytosis. He has demon- of autoantibodies directed against a Milan, as an associate professor in the strated a direct role of clathrin-mediated neuronal antigen. Follow-up studies re- Department of Medical Pharmacology. budding in synaptic vesicle biogenesis vealed that the autoantibodies were tar- De Camilli continued his fruitful collab- (12), provided new mechanistic insights geted against the GABA-synthesizing oration with Greengard, and he also into the function of dynamin in the fis- enzyme, glutamic acid decarboxylase commuted to Yale for short periods of sion reaction (13), and identified and (GAD) (26, 27) and that anti-GAD anti- teaching and research. Regarding his characterized several factors that assist bodies are also found in the majority relationship with Greengard, De Camilli clathrin and dynamin in their actions of patients with insulin-dependent dia- said, that ‘‘the enthusiastic support and (14–20). betes mellitus (28). ‘‘The most exciting trust that he put in me was a major In what De Camilli considers one of moment was late one night at the micro- driving force for the success in my ca- his important achievements, he demon- scope when we realized that this patient reer.’’ De Camilli remained at the Uni- strated the key role of interfaces be- had antibodies to an antigen, GAD, versity of Milan for six years, but, after tween cytosolic proteins and the lipid shared by pancreatic ␤ cells and by in- a sabbatical with Paul Greengard at bilayer in the acquisition of membrane hibitory neurons, and this patient had Rockefeller in 1987, he returned to the curvature during endocytosis (17, 20– symptoms of both pancreatic ␤ cell dys-

8260 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0403132101 Bundesen Downloaded by guest on September 29, 2021 function and a neurological disease ated protein that is sometimes expressed ogy to add a dynamic dimension to our BIOGRAPHY thought to result from an impairment of abnormally by breast cancer cells (29). understanding of molecular and subcel- GABA-ergic synapses,’’ he said. The In the future, De Camilli hopes to lular processes,’’ he said. ‘‘I also would detection of anti-GAD autoantibodies take the wealth of knowledge that re- like to be part of an effort to bring back subsequently has proven valuable in the searchers have accumulated through cell biology and molecular mechanisms diagnosis of both stiff-man syndrome molecular biology studies, especially re- to the context of the whole organism. I and insulin-dependent diabetes mellitus. search in genomics, proteomics, and the see this as the major wave of the future. De Camilli and his colleagues further emerging field of ‘‘lipidomics,’’ and ap- It is a rediscovery of physiology at the discovered that stiff-man syndrome can ply this information to his own field organismal level, but now we under- occur in conjunction with breast cancer with an emphasis on synaptic physiol- stand the molecular mechanisms.’’ when autoimmunity is directed against ogy. ‘‘I am interested in exploiting the amphiphysin, a synaptic vesicle-associ- powerful new imaging tools of cell biol- Liza Bundesen, Science Writer

1. Wenk, M. R. & De Camilli, P. (2004) Proc. Natl. 14. McPherson, P. S., Garcia, E. P., Slepnev, V., 23. Cremona, O., Di Paolo, G., Wenk, M., Luthi, A., Acad. Sci USA 101, 8262–8269. David, C., Zhang, X., Grabs, D., Sossin W. S., Kim, W. T., Takei, K., Daniell, L., Nemoto, Y., 2. De Camilli, P., Peluchetti D. & Meldolesi, J. Bauerfeind, R., Nemoto, Y. & De Camilli, P. Flavell, R. A., McCormick, D. A. & De Camilli, P. (1974) Nature 248, 245–246. (1996) Nature 379, 353–357. (1999) Cell 99, 179–188. 3. De Camilli, P., Peluchetti, D. & Meldolesi, J. 15. Shupliakov, O., Lo¨w, P., Grabs, D., Gad, H., Chen, 24. Wenk, M. R., Pellegrini, L., Klenchin, V. A., Di (1976) J. Cell Biol. 70, 59–74. H., David, C., De Camilli, P. & Brodin, L. (1997) Paolo, G., Chang, S., Daniell, L., Arioka, M., 4. De Camilli, P., Macconi, D. & Spada, A. (1979) Science 276, 259–263. Martin, T. F. & De Camilli, P. (2001) Neuron 32, Nature 278, 252–254. 16. Chen, H., Fre, S., Slepnev, V. I., Capua, M. R., 79–88. 5. De Camilli, P., Cameron, R. & Greengard, P. Takei, K., Butler, M. H., Di Fiore, P. P. & De 25. Di Paolo, G., Pellegrini, L., Letinic, K., Voronov, (1983) J. Cell Biol. 96, 1337–1354. Camilli, P. (1998) Nature 394, 793–797. S., Chang, S., Wenk, M. R. & De Camilli, P. (2002) 6. De Camilli, P., Harris, S. M., Huttner, W. B. & 17. Takei, K., Slepnev, V. I., Haucke, V. & De Camilli, Nature 420, 88–89. Greengard, P. (1983) J. Cell Biol. 96, 1355–1373. P. (1999) Nat. Cell Biol. 1, 33–39. 26. Solimena, M., Folli, F., Denis Donini, S., Comi, 7. Huttner, W. B., Schiebler, W., Greengard, P. & De 18. Ringstad, N., Gad, H., Low, P., Di Paolo, G., G. C., Pozza, G., De Camilli, P. & Vicari, M. Camilli, P. (1983) J. Cell Biol. 96, 1374–1388. Brodin, L., Shupliakov, O. & De Camilli, P. (1999) (1988) New Engl. J. Med. 318, 1012–1020. 8. Navone, F., Jahn, R., Di Gioia, G., Stukenbrok, Neuron 24, 143–154. 27. Solimena, M., Folli, F., Aparisi, R., Pozza, G. & H., Greengard, P. & De Camilli, P. (1986) J. Cell 19. Haucke, V. & De Camilli, P. (1999) Science 285, De Camilli, P. (1990) New Engl. J. Med. 322, Biol. 103, 2511–2527. 9. Cameron, P. L., Su¨dhof, T. C., Jahn, R. & De 1268–1271. 1555–1560. Camilli, P. (1991) J. Cell Biol. 115, 151–164. 20. Farsad, K., Ringstad, N., Takei, K., Floyd, S. R. 28. Baekkeskov, S., Aanstoot, H. J., Christgau, S., 10. Matteoli, M., Takei, K., Perin, M. S., Su¨dhof, T. C. & De Camilli, P. (2001) J. Cell Biol. 155, 193– Reetz, A., Solimena, M., Cascalho, M., Folli, F., & De Camilli, P. (1992) J. Cell Biol. 117, 849–861. 200. Richter-Olesen, H. & De Camilli, P. (1990) Nature 11. Burton, J., Roberts, D., Montaldi, M., Novick, P. 21. Takei, K., Haucke, V., Slepnev, V., Farsad, K., 347, 151–156. & De Camilli, P. (1993) Nature 361, 464–467. Salazar, M., Chen, H. & De Camilli, P. (1998) Cell 29. Folli, F., Solimena, M., Cofiell, R., Austoni, 12. Takei, K., Mundigl, O., Daniell, L. & De Camilli, 94, 131–141. M., Tallini, G., Fassetta, G., Bates, D., Cart- P. (1996) J. Cell Biol. 133, 1237–1250. 22. Lee, E., Marcucci, M., Daniell, L., Ochoa, G. C., lidge, N., Bottazzo, G. F., Piccolo, G. & De 13. Takei, K., McPherson, P., Schmid, S. L. & De Farsad, K. & De Camilli, P. (2002) Science 297, Camilli, P. (1993) New Engl. J. Med. 328, 546– Camilli, P. (1995) Nature 374, 186–190. 1193–1196. 551. CELL BIOLOGY

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