Our lab is interested in the cells at the edges of the distribution. The ones do not look like the others, often labeled at ‘weird’, and easily overlooked in most conventional approaches that only consider the behavior of the average cell. Our underlying hypothesis is that a lot of biology exists at the edges, and sometimes, the most interesting cells exist far away from the population average. We apply this thinking to pathogenesis, in which there are clear examples of rare subpopulations playing important roles.
We study mycobacteria. The most famous mycobacteria, Mycobacterium tuberculosis, causes tuberculosis, the world’s deadliest infectious disease. Part of the reason for M.tuberculosis’s success as a pathogen is that it can exhibit a tremendous amount of variability even in a genetically identical population. This diversity allows the pathogen to survive the stresses imposed by the host and by the antibiotics used to treat the disease.
Our lab uses a variety of techniques – from parallel transposon sequencing to super-resolution microscopy – to discover the strategies mycobacteria use to grow and survive. We hope that what we learn will be helpful in designing new tuberculosis therapeutics designed to kill the infection faster and more completely.
Most projects in the lab can be broadly classified into two categories:
1 – What are the differences between genetically identical bacteria? How do these differences arise?
Like many other organisms, one way mycobacteria create diversity is through asymmetric cell division. We have discovered that deletion of a single gene, which we named LamA (for Loss of Asymmetry Mutant A), creates cells that divide more symmetrically, leading to a more uniform population. Many of the projects in the lab are related to uncovering the molecular mechanisms of asymmetric cell division.
2 – What is this heterogeneity good for?
How variability is overcome or used in biological systems is a fundamental question. Our lab seeks to understand how the diversity we see in bacterial populations is related to their pathogenic lifecycle. Along these lines we ask how diversity is used to generate antibiotic tolerance, antibiotic resistance, and survival in the host.