Our laboratory performs a combination of theoretical and experimental studies at the interface of physics and biology, in an emerging research area known as quantitative biology, whose overall goal is to attain quantitative, predictive understanding of living systems. The focus of our lab is on bacteria, the simplest autonomous living systems, which nevertheless defy quantitative, predictive understanding at multiple levels, e.g., from molecular characteristics to cellular behaviors, and from cellular characteristics to population- and community- wide dynamics.
Since the birth of molecular biology, a basic scientific paradigm towards understanding biological functions has been to elucidate the underlying molecular interactions. However, despite the many thousands of interactions revealed by rapid advances in ’omics technologies, many basic functions of living cells remain mysterious under this “bottom-up” approach. Over a decade ago, our lab pursued a complementary “top-down” approach, starting with quantitative characterization of physiological behaviors of cells. Simple phenomenological models of bacterial growth control, built on empirical observations of growth-rate dependent proteome allocation, were formulated to make quantitatively accurate, parameter-free predictions relating protein expression and cell growth for the model bacterium E. coli under a variety of environmental and genetic perturbations (Scott et al, Science 2010, Deris et al, Science 2013). Quantitative methods of proteome analysis have since been developed to validate and establish simple rules of proteome allocation assumed for a broad range of growth conditions (Hui et al, MSB 2015; Mori et al, MSB 2021). Extension of our approach has led to quantitative physiological understanding of a number of long-standing bacterial phenomena including catabolite repression (You et al, Nature 2013), diauxic shift (Erickson et al, Nature 2017), and metabolic overflow (Basan et al, Nature 2015), as well as uncovering new phenomena, such as tradeoff between fast growth and rapid adaptation (Basan et al, Nature 2020) and hierarchical recovery of biosynthesis during adaptation from rich to minimal media (Wu et al, Nature Microb. 2023). Quantitative top-down approaches have also enabled elucidation of molecular strategies underlying global regulation, including cyclic-AMP signaling (You et al, Nature 2013), ppGpp signaling (Wu et al, PNAS 2022), and transcription-translation coordination (Balakrishnan et al, Science, 2022). This line of research, reviewed by Scott & Hwa (2022), showcases the effectiveness of quantitative phenomenology in both connecting seemingly unrelated behaviors and predicting new behaviors, and in elucidating the strategies and functions of complex molecular regulation. Overall, we view quantitative phenomenology as a necessary first step towards attaining a systemic understanding of living systems, as Kepler’s laws of planetary motion are to Newton’s theory of gravity, and as the laws of thermodynamics is to statistical mechanics.
In the past several years, we have further extended our quantitative physiological approaches to study spatiotemporal dynamics of bacterial population and their evolution, in the context of biofilm formation (Warren et al, eLife 2019) and chemotactic exploration (Cremer et al, Nature 2019; Liu et al, Nature 2019). We have also expanded our studies beyond model organism in ideal laboratory conditions, to e.g., gut microbes in colonic flow environment (Cremer et al, PNAS 2016; Cremer et al, PNAS 2017) and under acid stress (Taylor et al, in review). We are further investigating microbial growth on heterogeneous substrates (Guessous et al, in review) and metabolic interactions within communities (Amarnath et al, in review). The latter studies are taken in the context of marine microbial communities, in collaboration with the PriME Consortium supported by the Simons Foundation.
Current research activities are in the following areas:
- Bacterial stress response: Why don’t cells grow well despite having plenty of nutrients when placed in “stressful” (e.g., high salt or low pH) conditions? Existing studies of cellular responses to stress largely follow the bottom-up paradigm, focusing on what genes are turned on and what these genes do. We focus instead on what cells do and why they do what they do physiologically, using quantitative phenomenological approaches. Such studies are revealing previously unappreciated new constraints living cells are subjected to, along with new molecular strategies cells employ to cope with them. An example is reported here.
- Non-growing bacteria: Bacteria spend most of their lives not growing, due to either nutrient depletion or various forms of stress that prevent normal nutrient utilization. What do they do to maintain viability in non-growing conditions? What are the consequences of these actions when growth-permitting conditions return? Again, we take quantitative physiological approaches which complement the traditional gene-centric focus, revealing novel bacterial strategies with important consequences on the growth-survival tradeoff.
- Characterizing distinct bacterial physio-types: We have performed a preliminary survey of global physiological characteristics (“physio-types”) for a spectrum of bacterial species across bacterial phylogeny. Interestingly, vastly diverging species can share quantitatively similar characteristics, while closely related species can be quite distinct. We know very well the physio-type represented by E. coli, but know very little about the other physio-types. Efforts are underway to elevate the knowledge of some selected physio-types in par with our knowledge for E. coli.
- Interacting microbial communities: Understanding the complexity of microbial communities has emerged as a central challenge in microbiology in recent years. At the same time, the subject is attracting the attention of an increasing number of physicists. The conceptual basis for current ideas on community organization was laid down by theoretical ecologists 50 years ago, based on criteria for the existence of steady state involving many species. Our recent study on simple toy systems refute the steady-state framework and point to the importance of focusing on dynamics, with the community experiencing different dynamical phases, and different species behaving differently in different phases. The three topics listed above are in fact all single-species characteristics deemed important for understanding community dynamics. Our aim is to incorporate quantitative knowledge of distinct bacterial physio-types to establish a new conceptual framework to understanding the complex dynamics of microbial communities.