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Terence T. Hwa

Research

Current activities in our lab are in the area of quantitative and systemic biology. This is an emerging area of research at the interface of biology, biochemistry, engineering, and physics. In this post-genome era, it is clear that the complexity of a biological organism resides not merely in the intricacies of its components (e.g., proteins), but more importantly in the array of interactions these components can have with each other. This shift of paradigm is initiating a revolution in biology: Instead of focusing on genes, proteins, and pathways, bioloigsts are beginning to think in terms of modules and networks. However, a significant challenge lies in the fact that much of the interactions of the subsystems are yet unknown.

Our research is focused on microbiology, particularly on the bacterium E. coli which is the best characterized living organism both molecularly and physiologically. In the long run, we wish to develop a comprehensive understanding of the organism, i.e., understanding its physiological response under various growth conditions in molecular terms. However even for E. coli, a global approach seems premature in our opinion due to the many missing molecular players and interactions. Thus, we work on smaller sub-systems, with the insistence on developing quantitative links from molecules all the way to cell physiology. Our emphasis can be regarded as the "vertical approach", which complements the "horizontal approach" favored by the 'omics technology. An introduction to our vertical, quantitative approach is described in a recent course on quantitative molecular biology developed by our laboratory.

Vertical integration requires a command of the vast knowledge accumulated over many decades of research in molecular and microbiology, as well as a combination of experimental and theoretical efforts. Some of the experiments are being carried out in our own lab; others are done together with biology collaborators. Our experiments are often theory-motivated, yet discoveries made in the lab has inspired fresh theoretical view points. In similar ways, our theoretical studies play the dual role of analyzing experimetal results and guiding new generation of experiments. The close interaction between theory and experiment allows the theorists to be in contact with biological reality, and allows the experimentalists to have a good sense of the power (and limitations) of quantitative analysis. In this way, we hope to train a new generation of scientists who can freely exploit opportunities at the interface between biology and physics.

Below are some topics our lab has been working in recent years; all projects involve experimental and theoretical components.

  • gene regulation: quantitative characterization of combinatorial transcriptional control; de novo synthesis of novel transcriptional control; quantitative characterization of post-transriptional control by regulatory small RNA;
  • protein-protein interaction: specificity and cross-talk in two-component signaling; assembly of macromolecular complexes;
  • molecular evolution: directed evolution of promoters, cis-regulatory sequences, and signaling molecules; analysis of evolved seqeunces to deduce rules of molecular interaction;
  • genetic circuits: quantitative characterization of various endogenous genetic circuits; synthesis and characterization of artificial circuits;
  • metabolic control: interaction and coordination of metabolic pathways; systems being studied include carbon/nitrogen metabolism, aerobic/anarobic control, Fe/oxidative stress;
  • physiology & cell growth:coordination of growth and metabolic activities; control of ribosome synthesis and cell growth; control of cell division.

Publications

  • M. Scott, C. W. Gunderson, E. Mateescu, Z. Zhang and T. Hwa (2010). Inter-dependence of Cell Growth and Gene Expression: Origins and Consequences. Science, accepted.
  • A. Schug, M. Weigt, J.N. Onuchic, T. Hwa, and H. Szurmant (2009). High resolution protein complexes from integrating genomic information with molecular simulation. PNAS106:22124-22129.
  • S. Klumpp, Z. Zhang and T. Hwa (2009). Growth-rate dependent global effects on gene expression in bacteria.Cell139:1366-1375.
  • U. Gerland and T. Hwa (2009). Evolutionary Selection Between Deifferent Modes of Gene Regulation.PNAS106:8841-8846.
  • S. Klumpp and T. Hwa (2008). Stochasticity and traffic jams in the transcription of ribosomal RNA: Novel role of termination and antitermination. PNAS105:18159-18164.
  • E. Levine, Z. Zhang, T. Kuhlman, and T. Hwa (2007). Quantitative Characteristics of Gene Regulation Mediated by small RNA. PLoS Biol5:e229.
  • N.E. Buchler, U. Gerland, and T. Hwa (2005). Nonlinear protein degradation on the funtions of genetic circuits. PNAS102:9559-9564.
  • N. Buchler, U. Gerland and T. Hwa (2003). On Schemes of Combinatorial Transcription Control. PNAS100:5136-5141.

Biography

Dr. Terence Hwa has a joint appointment as a Professor in the Department of Physics at U.C. San Diego. He is a Distinguished Visiting Professor at the University of Hong Kong, in Hong Kong, China.