Professor Thomas Kuhlman received his Ph.D. in physics from the University of California, San Diego in 2007. While at UCSD he worked at the interface of theoretical physics and experimental biology, studying and validating statistical mechanical models of transcriptional and post-transcriptional gene regulation in the bacterium Escherichia coli.
From 2008 to 2012 he was a postdoctoral fellow in the Department of Molecular Biology at Princeton University.
My research involves the interplay of theoretical physics and in vivo experimental biology. My experimental work is primarily in the model bacterium E. coli, as its fundamental biological processes and their components are sufficiently well understood to allow their theoretical description to be tractable. We aim to combine cutting-edge single molecule microscopy and quantitative gene expression measurements to inform the construction of theoretical models describing the interaction of transcription factors (TFs) and other proteins with DNA in living cells, and then use these theoretical models to motivate further experiments.
The Biophysics of Gene Regulation and Consequences for Genome Organization
Remarkably, in the 4.6 million base pairs that make up the E. coli genome, the gene that encodes the prototypical TF protein Lac Repressor is located only ~100 base pairs upstream of the DNA target to which it binds to regulate the expression of the metabolic lac genes. Bioinformatic analyses of the E. coli transcriptional regulatory network verify that TF genes are generally found more frequently near their regulatory targets than would be expected if genes were distributed randomly on the chromosome. By disrupting and rearranging the spatial and genomic organization of regulatory networks in E. coli, my lab attempts to directly observe, quantify, and theoretically describe potential biophysical forces that determine the architecture and organization of genomes.
Transposon Propagation Through Populations
Transposons are mobile genetic elements present in all domains of life that are able to spontaneously change their position within the genome. They compose a significant fraction of "junk DNA" in human cells, and due to their inherently mutagenic nature are implicated in many diseases such as hemophilia, porphyria, and muscular dystrophy. We have developed a synthetic inducible transposon that, when integrated into the chromosome of E. coli, allows us to watch in real time the dynamics of transposon propagation through the population, and to study the rates of propagation and the statistics of re-integration and mutation.
Molecular Engineering of Tools for in vivo Genome Manipulation
To facilitate the manipulation of the organization of the E. coli genome, I have engineered simple molecular tools that allow the precise integration of very large synthetic gene constructs into any desired location of the E. coli chromosome. These tools have been distributed to dozens of labs around the world and licensed to several commercial biotech companies; please contact Addgene to request them for use in your lab. My lab is further developing these and other tools to improve their flexibility, efficiency, ease of use, and applicability to additional organisms.