- Gordon McKay Professor of Applied Physics and Professor of Molecular and Cellular Biology
The Needleman laboratory investigates how the cooperative behaviors of molecules give rise to the architecture and dynamics of self-organizing subcellular structures. These collective effects are not only directly relevant to cellular organization, they also raise a number of fascinating questions concerning the mechanics and statistical physics of these highly non-equilibrium systems. Our long term goal is to use our knowledge of subcellular structures to quantitatively predict biological behaviors and to determine if there are general principles which govern these non-equilibrium steady-state systems.
Our work currently focuses on studying the spindle, the self-organizing molecular machine that segregates chromosomes during cell division. The spindle is a dynamic steady-state structure composed of a plethora of molecules, most notably DNA, which is compacted into chromosomes, and the protein tubulin, which forms long fibers, called microtubules, which are oriented into a bipolar array that constitutes the bulk of the spindle. Even though the overall structure of the spindle can remain unchanged for hours, the molecules that make up the spindle undergo rapid turnover with a half-life of tens of seconds or less, and if the spindle is damaged, or even totally destroyed, it can repair itself. While many of the individual components of the spindle have been studied in detail, it is still unclear how these molecular constituents self-organize into this structure and how this leads to the internal balance of forces that are harnessed to divide the chromosomes.
Research in the Needleman laboratory is focused on three complementary areas:
- We are using a range of methods, from magnetic tweezers, to laser ablation, to high resolution microscopy and fluorescence spectroscopy, to study the behavior of chromosomes in the spindle. These quantitative measurements are combined with biochemical and genetic perturbations, and theoretical analysis, to understand the forces acting on chromosomes, the connections between mechanics and signaling, and the processes that lead to accurate chromosome segregation.
- We are working to understand the non-equilibrium dynamics that produce the architecture and dynamics of the spindle. This has lead us to investigate the self-organization of microtubules and molecular motors more generally, including in reconstituted systems of purified components. We are studying the dynamics, mechanics, and thermodynamics of these systems, and investigating how the large scale behaviors of these active materials depend on the properties of their molecular constituents.
- We are studying chromosome segregation errors in mouse and human eggs and early embryos, which are responsible for age related infertility in females. We are focusing on testing the hypothesis that these errors are caused by defects in mitochondria metabolism. This work has lead us to develop quantitative, non-invasive methods to probe mitochondria; to construct and test coarse grained models of mitochondria function; and to investigate oogenesis and pre-implantation embryo development more broadly. We aim to develop a quantitative, biophysical understanding of these fundamental process and to improve treatments of human infertility.
Our work entails a close connection between quantitative experiments, theory, and simulations, and involves extensive technique development.