Understanding Microtubules Self-Assembly Kinetics May Lead to Better Cancer Treatment

Posted May 2012

Photo courtesy of Indiana University.

Microtubules are hollow rods approximately 25 nanometers in diameter. They undergo continual assembly and disassembly within a living cell and serve as long-distance "superhighways" for motor-based intracellular transport. The dynamics of microtubule self-assembly are of great interest for medical reasons since microtubule assembly-promoting drugs are used to treat cancer. More recently, they have been used to suppress artery reclosure after stenting.

The study of microtubules goes back several decades. For more than 40 years, a classic model put forward by Oosawa has been widely used to interpret the kinetics of self-assembly data for a wide range of biopolymers, including microtubules. While visiting the IMA in early 2008, David Odde from the Department of Biomedical Engineering at the University of Minnesota, his then-student Melissa Gardner (now University of Minnesota assistant professor of genetics, cell biology, and development), and Imre Janosi from the Department of Physics of Complex Systems at the Lorand Eotvos University in Budapest, Hungary, examined the surprisingly large variability in recent laser-tweezers data collected in Alan Hunt’s lab at the University of Michigan. They began to suspect that the subunit addition-loss rates at the tip of a microtubule cannot predicted by the 40-year-old model.

At the IMA, they performed careful numerical simulations of microtubule kinetics using a simple two-dimensional model developed by Odde in 2002. These simulations predicted the laser-tweezers data, as well as new Total-Internal-Reflection Fluorescence Microscopy data having nanometer-scale resolution, obtained by Gardner in Joe Howard’s lab at the Max Planck Institute in Dresden, Germany. Their calculations were able to predict the data, and in the process, they obtained a better understanding of the self-assembly mechanism. What they found was that the rates of subunit addition and loss are 10 times greater than previously estimated.

The results of their investigation appeared in the August 19, 2011, issue of the journal Cell. The importance of their work may lay in future development of improved cancer treatments, the development of which can now be guided by an improved understanding of the fundamentals of microtubule assembly.