The Hansen lab studies gene expression dynamics by employing techniques at the interface of computational modeling, cell-free biochemistry, and quantitative single-cell biology.
Our goal is to identify design principles that allow for robust outcomes in noisy crowded systems.
CELLS ARE NOISY SYSTEMS
In Biology, a truly random process translates to the random collision between, and consequent reaction of molecules. However, gene expression is far more complex and not simply governed by the random collision of molecules. In fact, we know that unless tightly regulated, cell-to-cell variability (i.e. noise) in mRNA and protein levels is far greater than expected from the random collision of molecules. This noise can drive cell-fate decisions and hamper the treatment of HIV and cancer. In our lab we aim to identify the biophysical properties of cells, as well as gene-circuit features that impact cell-to-cell variability.
Video: Time-lapse video of HIV infected T-cells expressing GFP and mCherry tagged viral proteins.
SINGLE MOLECULE IMAGING: FROM KINETICS TO CIRCUITS
Single-molecule fluorescence in situ hybridization (smFISH) is a powerful imaging technique that allows for the quantification of absolute numbers of RNAs across hundreds to thousands of cells, while maintaining information about the 3D location of each transcript within a single cell at a nanometer-scale accuracy. This precise information enables us to calculate rates for every biochemical step in mRNA biogenesis (read more about this here). In addition, smFISH permits the differentiation between alternate splicing mechanisms from which we can deduce underlying feedback architectures. Curious about how this can be done? Read our recent review.
Video: 3D rendering of a single cell with fluorescently labeled mRNA molecules. DNA is stained in blue, nuclear mRNA in green, and cytoplasmic mRNA in red.
EXPLOITING CELL MIMICS TO STUDY CELLULAR REACTIONS
We have developed a robust method to study gene expression kinetics and noise in vitro using droplet microfluidics. Cell-free biochemistry is the optimal platform to elucidate the complexity of cellular systems from the simplicity of mathematical models. Through our minimalistic cell mimics, we strategically study biophysical properties – such as diffusion and confinement – that influence gene expression kinetics and noise (read more here and here).
Video: Time-lapse movie demonstrating successful GFP expression in synthetic cell mimics.
MODELING CELLULAR REACTIONS
We aim to bridge the gap between theory and experiment by incorporating iterative combinations of experimental and computational investigation into all our research. As a result, we can pinpoint the causes underlying our experimental observations, driving new hypotheses and experimental testing. We have successfully applied this approach in a range of projects from identifying the physical properties that impact reaction and diffusion kinetics of cellular processes, to gene-circuit motifs that modulate gene expression variability.
Video: Simulation showing a promoter switching between an on and off state (top), and corresponding effect on mRNA (middle) and protein expression (bottom).
Interested in our work? We always welcome collaborations that complement our research interests.