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HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Nat Rev Manuscript Author Mol Cell Biol. Manuscript Author manuscript; available in PMC 2016 November 20. Published in final edited form as: Nat Rev Mol Cell Biol. 2016 April 22; 17(5): 322–328. doi:10.1038/nrm.2016.45. Microtubules: 50 years on from the discovery of tubulin Gary Borisy Forsyth Institute, 245 First Street, Cambridge, Massachusetts 02142, USA. [email protected] Rebecca Heald Division of Cell and Developmental Biology and Molecular and Cell Biology Department, University of California, Berkeley, California 94720, USA. [email protected] Jonathon Howard Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06510, USA. [email protected] Carsten Janke The contributors* Gary Borisy completed his Ph.D. in 1966 at the University of Chicago, Illinois, USA, and was formerly a member of faculty at the University of Wisconsin and Northwestern University, USA, and President/Director of the Marine Biological Laboratory, Massachusetts, USA. He is best known for his work on the molecular biology of the cytoskeleton. Currently, he is a Senior Investigator at the Forsyth Institute in Cambridge, Massachusetts, and is exploring the biogeography of microbial communities at the micrometre scale through combinatorial labelling, spectral imaging and metagenomics. Gary Borisy's homepage: http://forsyth.org/person/scientist/gary-borisy Rebecca Heald is a Professor in the Department of Molecular and Cell Biology at the University of California Berkeley, USA. She pursued her Ph.D. training with Frank McKeon at Harvard University, Cambridge, Massachusetts, USA, and carried out postdoctoral work with Eric Karsenti at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany. Her laboratory is interested in mechanisms of spindle assembly, cell division and size control. Jonathon Howard has a Ph.D. from the Australian National University in Canberra, Australia, and was Professor of Physiology and Biophysics at the University of Washington in Seattle, USA, before joining the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, as a group leader and director. The Howard laboratory recently moved to Yale University, New Haven, Connecticut, USA. His research interests include molecular motors and cytoskeletal polymers, especially their roles in mitosis, in ciliary and flagellar motility and in neuronal architecture. Jonathon Howard's homepage: http://medicine.yale.edu/mbb/faculty/jonathon_howard.profile Carsten Janke studied biochemistry at the University of Leipzig, Germany. After his Ph.D. in neurochemistry, he held several postdoctoral positions in France and Scotland, working on DNA–protein interactions, on kinetochore complexes in budding yeast and, finally, on post-translational modifications of tubulin, a subject that became his major research focus. He started his first independent group in 2005, and his team discovered most of the enzymes involved in post-translational polyglutamylation and polyglycylation of tubulin. Today, the team of Carsten Janke is trying to decipher the tubulin code, by employing an interdisciplinary approach from basic biochemistry to the study of mouse models. Carsten Janke was elected a European Molecular Biology Organization (EMBO) member in 2014. Carsten Janke's homepage: https://perso.curie.fr/Carsten.Janke/ Andrea Musacchio is Director of the Department of Mechanistic Cell Biology at the Max Planck Institute of Molecular Physiology in Dortmund, Germany. After his studies at the University of Rome Tor Vergata, Italy, Musacchio carried out doctoral work with Matti Saraste at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and postdoctoral work with Stephen C. Harrison at the Harvard Medical School in Boston, Massachusetts, USA. Since establishing his research group (initially in Milan, Italy, and now in Dortmund), Musacchio has been investigating the molecular basis of the attachment of chromosomes to spindle microtubules during mitosis, as well as the feedback control mechanisms that regulate this process. Eva Nogales obtained her B.S. in Physics (Autonomous University of Madrid, Spain) and her Ph.D. in Biophysics (University of Keele, Staffordshire, UK), working at the Synchrotron Radiation Source, UK. As a postdoctoral researcher with Ken Downing at the Lawrence Berkeley National Laboratory (LBNL), California, USA, she described the first atomic structure of tubulin. She is a Molecular and Cell Biology Professor at the University of California Berkeley, a Faculty Scientist at LBNL, and a Howard Hughes Medical Institute (HHMI) Investigator. Her laboratory uses cryoelectron microscopy to study microtubule structure, dynamics and interactions, as well as macromolecular assemblies involved in gene regulation. Eva Nogales' homepage: http://cryoem.berkeley.edu *Listed in alphabetical order Competing interests statement The authors declare no competing interests. Borisy et al. Page 2 Institut Curie, PSL Research University, CNRS UMR3348, Centre Universitaire, Bâtiment 110, Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author F-91405 Orsay, France. [email protected] Andrea Musacchio Department of Mechanistic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn- Strasse 11, 44227 Dortmund, Germany; and the Centre for Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Universitätsstrasse, 45141 Essen, Germany. [email protected] Eva Nogales Biochemistry, Biophysics and Structural Biology Division, Molecular and Cell Biology Department, University of California, Berkeley, California 94720-3220, USA; the Howard Hughes Medical Institute, Maryland, USA; and the Lawrence Berkeley National Laboratory, USA. [email protected] Abstract Next year will be the 50th anniversary of the discovery of tubulin. To celebrate this discovery, six leaders in the field of microtubule research reflect on key findings and technological breakthroughs over the past five decades, discuss implications for therapeutic applications and provide their thoughts on what questions need to be addressed in the near future. Identifying the main component of microtubules was obviously the pressing task in the field around 50 years ago. What key questions were being pursued when you entered the arena of microtubule research? Gary Borisy. Actually, I had no idea in the early 1960s that I was entering the arena of microtubule research, because it hadn't yet been defined as an arena. Although the term `microtubule' was first coined in 1963, the structures had not, in fact, been observed in most cells, because the fixation methods used at the time did not preserve them. It was only after the introduction of glutaraldehyde as a fixative, also in 1963, that they began to be observed routinely. The concept of the microtubule as a `ubiquitous' cytoskeletal structure wasn't put forward until 1965. My entry point into the field was mitosis: I wanted to get a molecular handle on how cells divide. Working with Ed Taylor at the University of Chicago (Illinois, USA), we were trying to identify and purify the molecule that bound to colchicine, because colchicine was known to specifically inhibit mitosis. We had no preconceived idea about what the colchicine target would be, but we believed that identifying the target would teach us something important about mitosis. So, the key questions for us at the time were how to isolate, purify and characterize the colchicine-binding protein and then to establish its identity1,2. Rebecca Heald. In the mid-1990s, one pressing question was why microtubules in cells were so much more dynamic than microtubules assembled from purified tubulin. Neuronal microtubule-associated proteins (MAPs) had been identified and studied (in large part because they co-purified with tubulin isolated from brain tissue, where it is most abundant), but these proteins all stabilized microtubules, and factors that induced the transition from growth to shrinkage (catastrophe) were unknown. A related question was how the Nat Rev Mol Cell Biol. Author manuscript; available in PMC 2016 November 20. Borisy et al. Page 3 microtubule cytoskeleton transformed from a relatively stable interphase array to a highly Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author dynamic bipolar spindle in mitosis. At the time, the centrosome was thought to be the sole `microtubule-organizing' centre of the cell, determining the site of microtubule growth and their polarized orientation. In my opinion, the discovery of a large family of kinesin motor proteins, as well as cytoplasmic dynein, spawned key investigations into how cellular factors affect microtubule behaviour. The diverse activities of different motor proteins to induce catastrophe, crosslink and move microtubules relative to one another revealed the ability of microtubule arrays to `self-organize'. This process allows the spindle to form in the absence of centrosomes — for example, during female meiosis in many animal species, or when the centrosome is inactivated genetically or by laser ablation. An important ongoing challenge is to fully understand how microtubule dynamics and organization emerge from a defined set of proteins through reconstitution experiments. Jonathon Howard. One of the big questions back when I got into the microtubule business, around 1990, was how motor proteins such as kinesin and dynein