Research in my lab focuses on the mechanisms that govern mitotic spindle assembly and centrosome duplication. We have been continuously supported by the NIH since 1999, and the key to this success was our focus on high-resolution microscopy studies in live cells. A new theme that emerged from the years of our work on cell division is that every aspect of mitotic spindle assembly is enacted by multiple molecular mechanisms. These mechanisms work in concert and provide efficient back-ups for one another. Such a multiplicity creates a fail-safe system with numerous redundancies. Individual deficiencies in specific molecular cascades are compensated for by up-regulation of alternative mechanisms so that the exact mode of spindle assembly varies in different cell types and in normal vs. transformed cells. Our research also revealed that geometric constraints imposed by the architecture of the kinetochores/centromere as well as spatial arrangements of chromosomes and centrosomes play a defining role in ensuring error-free chromosome segregation.
Over the years, our lab has mastered several sophisticated approaches for studying the cell cycle and mitosis. We pioneered the use of laser microsurgery on intracellular targets delineated by the expression of fluorescent proteins. Our studies are renowned for the extensive use of correlative LM/EM. In this approach, serial-section EM analyses are applied to centrioles and kinetochores whose behavior was followed by live-cell microscopy. Correlative LM/EM was instrumental in our work that proved dispensability of centrosomes for mitotic spindle assembly in mammalian cells. This approach also allowed us to discover that chromosomes congress via lateral interactions with microtubule bundles. At the risk of appearing arrogant, I state that only a very few labs have been able to achieve the same level of synergy between live-cell and structural approaches that in turn advances our understanding of mechanisms that ensure stability of the genome.