Project Summary/Abstract
Bacteria undergo dramatic cellular re-organizations in different environments. Understanding the non-genetic,
reversible plasticity of cellular organization is crucial to unraveling the whole-cell level algorithm of survival,
growth, adaptation, and infection of bacteria, with biomedical significance in combating pathogens that can
adapt to various niches and tolerate antibiotics in the human body. Cellular space is incredibly crowded with
biomolecules yet well-organized. However, we still lack a precise understanding of how cellular space is
organized to dictate cellular scale behaviors, physiology, and fitness. The long-term goal of my lab is to
delineate basic principles of how life at the cellular scale emerges from biomolecules and their interactions. In
the next five years, we will pursue this goal by gauging how key features of cellular organizations interconnect
with physiological states and fitness in bacterial cells, in model organisms such as E. coli, and human
pathogens such as P. aeruginosa.
The organization of the cell connects to its physiological state via a combination of physical, chemical, and
biological processes. We will try to disentangle this complexity by testing two fundamental hypotheses
suggested by our preliminary observations: (1) the membrane real-estate hypothesis – the cytoplasmic
membrane is so packed with proteins that the cell needs to fine-tune the density, composition, and
organization of the membrane proteins for optimizing cell fitness, and (2) the cellular surplus hypothesis – the
core biosynthetic machines have an excess amount that does not benefit steady-state growth, but rather is
beneficial for adaptation to a new environment. To better test these ideas, we will quantify and manipulate the
density, composition, and spatial organization of membrane proteins and the abundance of core biosynthetic
machines and examine their effects on physiological states such as growth, adaptation, and cell death. We will
use these results to test physical models that render possible optimality principles by collaborating with
theorists in membrane physics and operations physics. These tasks require expertise in both quantitative
experiments and modeling. Our lab’s experience in biophysics, bioengineering, and molecular biology will set
us in a unique position to perform the research and foster cross-field collaborations and interactions. We also
plan to publish and share new tools and datasets to be yielded throughout the research with the scientific
community, such as microfluidic devices, image analysis software, and databases of protein physical
properties. Whether these hypotheses will be verified, outcomes from these projects can help us bridge cellular
organization and physiology and understand better cellular adaptation, a branch of knowledge that can be
extended to studying other higher organisms.
