How do Immune Cells Make Choices? Insights from Following Gene Regulation at the Single Cell Level
Hao Yuan Kueh
California Institute of Technology
January 28, 2016
Foege N130A, Wallace H. Coulter Seminar Room
Engineered immune cells are emerging as promising therapeutic agents for cancer and other life-threatening diseases. The therapeutic efficacy of these cells would be greatly enhanced if we could precisely control their decisions to develop or differentiate in response to antigens; however, despite decades of work, the basic mechanisms controlling these critical fate decisions still remains poorly understood. To understand how immune cells make fate decisions, and how these decisions be controlled, I use quantitative imaging to follow the regulation of key immune fate regulatory genes in single, developing cells, and combine these measurements with mathematical modeling. Using this approach to study macrophage differentiation, I discovered a new mechanism that robustly stabilizes a slow-dividing differentiated state, which involves positive feedback between a regulatory gene and the cell cycle (Kueh et al., Science 2013). In separate studies on developing T-cells, I uncovered evidence for a new mechanism for controlling the timing of T-cell fate commitment, which involves slow processes acting on the chromatin state of a key regulatory gene (in preparation). These studies shed light into basic mechanisms responsible for immune cell fate control, and lay the groundwork for building tools to direct fate choices in therapeutic cells.
Hao Yuan Kueh is a quantitative biologist whose work lies at the interface of multiple disciplines, including immunology, cell biology and biophysics. As an undergraduate in Physics at Princeton University, he performed theoretical studies on noise and robustness in regulatory gene networks. After completing his undergraduate studies, Kueh enrolled in the Biophysics graduate program at Harvard. There, he did graduate research with Tim Mitchison, where he studied the assembly and disassembly of actin filaments in cells. By combining quantitative experimental and modeling approaches, he uncovered a novel mechanism for filament disassembly, involving catastrophic elimination of long filament segments. After his PhD, he became a postdoc at the California Institute of Technology, jointly in the labs of Ellen Rothenberg and Michael Elowitz. In his current work, he uses quantitative single-cell approaches to examine the mechanisms underlying cell fate control in the immune system.