Areas of Research: Biochemistry, Cell Biology, Development, Genetics, Microbiology & Virology
- Molecular Biology
355 Lewis Thomas Lab
How do organisms make such amazing and complex structures out of such simple building blocks? Our lab focuses on discovering the fundamental mechanisms by which self-assembly happens across a wide range of spatial scales, from atoms and metabolites to proteins and polymers to cells and communities. For example, by assembling nanometer-sized proteins into micron-sized cytoskeletal polymers, bacteria make the measurements necessary to achieve their characteristic shapes. We focus our attention on the cell biology of bacteria, whose awesome experimental power allows us to attack questions with an integrated combination of genetics, biochemistry, microscopy, genomics, quantitative analysis, and computation. Our interdisciplary efforts are aided by our wonderful group of Princeton friends and collaborators.
We work on a wide range of systems with the unified theme of undersanding both the mechanisms and functions of self-assembly. We are currently focusing on three inter-related areas:
Bacterial shape and cytoskeletal regulation
Spheres, rods, commas, helices, branches, cubes, stars are just some of the tremendous diversity of cell shapes found in the bacterial kingdom. To generate such a wide array of morphologies in a single cell, bacteria must organize growth in a tiny ~1 μm3 space. But how? Work from our lab and others has shown that the proteins of the bacterial cytoskeleton self-assemble into cellular-scale structures that play essential roles in virtually all cell biological processes. We are currently studying what proteins constitute the bacterial cytoskeleton, how cytoskeletal proteins assemble, and how they regulate processes such as cell shape, division, polarity, chromosome dynamics, metabolism, and pathogenesis. We have traditionally focused on the polarized bacterium Caulobacter crescentus, whose asymmetric shape and synchronizable cell cycle make it particularly attractive for cell biological studies. We also have several projects focused on the well-characterized bacterium E. coli, as well as the opportunistic human pathogen Pseudomonas aeruginosa. These directions also enable us to study the selective benefits that specific shapes and polymers confer to each species, letting us ask not only how each shape is generated, but why.
The cell biology of bacterial metabolism
Classically, metabolism has been thought of as a well-mixed process. But work from our lab has shown that metolic enzymes are highly organized within the cell. Why? We have shown that assembly into higher-order polymers is an important mechanism for regulating the activity of some enzymes such as CTP Synthetase, and that co-assembly of multiple enzymes can regulate the flux through metabolic networks. We are now combining imaging and quantitative analysis methods to understand how spatial and temporal organization influences the activity of individual enzymes and metabolic pathways. We are also harnessing these principles as new ways to synthetically engineer bacteria to produce high-value products such as biofuels.
The cell biology of pathogenesis and environmental sensing
How do bacteria sense and respond to their environment, to other bacteria, and to their hosts? We can now use microfluidics and other methods to engineer environments that better mimic the mechanical, chemical, and biological cues that bacteria naturally encounter. We found that the polar adhesion and motility structures of species such as Caulobacter crescentus and Pseudomonas aeruginosa are essential features that shape their colonization strategies. We are discovered that bacteria can sense and respond to their mechanical environments. We are currently studying how bacterial mechanosensation occurs and the role of bacterial organization in shaping bacterial interactions with their hosts and with other bacteria.