(4an) Mechanistic Study and Engineering of Biological Networks: a Systems Biology & Synthetic Biology Approach

My research aims to elucidate fundamental mechanisms underlying the diverse and complex functions of biological systems, and to engineer biological systems, through integrated mathematical modeling, computer simulation and web-lab experiments. I would like to make pioneering contributions to two intimately related and equally exciting new fields: systems biology, which examines the integrated properties emerging from the interaction of multiple components of a system, and synthetic biology, which relies on the construction of synthetic systems for testing biological hypothesis or for the development of biology related applications. More specifically, my research focuses on the following directions:

? Mechanisms for biological switches arising from multisite modifications of single molecules and their roles in higher-level biological modules.

? Design, construction, and evolution of synthetic systems of genetic circuits and microorganisms.

? System level modeling of metabolic networks and metabolic engineering.

Doctoral Research

My background is in process systems engineering, which involves the development of quantitative mathematical models and computational algorithms for the simulation, design and optimization of chemical processes. In particular, my Ph.D. thesis focused on scheduling, planning and design of chemical processes. Under the supervision of Professor Christodoulos Floudas at Princeton University, I developed new mathematical frameworks for the modeling and optimization of a variety of complex chemical processes, including

1. integrated design and scheduling of multi-purpose batch processes;
2. medium-range production scheduling of multiproduct plants;
3. planning of well platform developments;
4. scheduling of tanker lightering;
5. robust optimization approach for scheduling problems with uncertain data.

In addition, during the last year of my graduate study, I had an opportunity to work on a project aiming to elucidate the glucose signaling pathways in yeast using global gene expression data. In collaboration with Dr. James Broach's group in the Molecular Biology Department at Princeton, we developed a new computational framework to identify the complex network topology of glucose signaling pathways in yeast. Our analysis generated network topologies which are consistent with, and extensions of, known biological interactions in glucose signaling.

Postdoctoral Research

Greatly inspired by what I discovered through the above-mentioned project that my training in mathematical modeling and computational analysis are potentially very useful to biological research, I decided to shift to biology for my postdoctoral research. In Dr. George Church's lab at Harvard Medical School, I have been enjoying working with biologists and other researchers on the following projects.

1.Investigation of artificial microbial symbiosis with modeling and experiments.

2. Development of a bioinformatics pipeline for the automatic generation of whole-cell metabolic network models from genome annotations and application to the study of marine cyanobacterium Prochlorococcus marinus.

3. Study of mechanisms of biological switching arising from multisite modifications of single molecules.

Research Plan

Positioned at the interface of biology, applied mathematics and engineering, I am confident and eager to become an independent researcher working on fundamental questions in biology and on the development of new biotechnologies. I will continue and expand my current research in the following directions.

? Mechanisms of multi-site based ultrasensitivity; experimental testing of proposed ultrasensitivity model with multisite phosphorylations.

? Design and construct artificial genetic circuits, which may utilize multisite molecules with ultrasensitivity.

? System-level modeling and engineering of micro-organisms.

? Evolution of microbial cooperation.

Papers in completion and selected publications

Systems Biology and Synthetic Biology

1. X. Lin*, Y. Gao*, Y. Shi, & G.M. Church. *: Equal contributions. The sound of silence: biological switches through single protein multisite modifications. In preparation.

2. N.B. Reppas*, X. Lin*, J. Shendure, G.J. Porreca, & G.M. Church. *: Equal contributions. Evolution of microbial symbiosis: a synthetic system of two cross-feeding E. coli auxotrophs. In preparation.

3. A. Brandes*, X. Lin*, J. Zucker, & G.M. Church. *: Equal contributions. In silico reconstruction of metabolic networks from annotated genomes: a new MILP based approach and its application to marine cyanobacterium Prochlorococcus. In preparation.

4. J. Shendure, G.J. Porreca, N.B. Reppas, X. Lin, J.P. McCutcheon, A.M. Rosenbaum, M.D. Wang, K. Zhang, R.D. Mitra, & G.M. Church. Accurate multiplex polony sequencing of an evolved bacterial genome. Science 309, 1728?1732 (2005).

5. D. Segr`e, J. Zucker, J. Katz, X. Lin, P. D'haeseleer, W.P. Rindone, P. Kharchenko, D. Nguyen, M.A. Wright, & G.M. Church. From annotated genomes to metabolic flux models and kinetic parameter fitting. Omics 7, 301?316 (2003).

6. X. Lin, C.A. Floudas, Y. Wang, & J.R. Broach. Theoretical and computational studies of the glucose signaling pathways in yeast using global gene expression data. Biotechnol. Bioeng. 84, 864?886 (2003).

Chemical Process Systems Engineering

7. C.A. Floudas & X. Lin. Continuous-time versus discrete-time approaches for scheduling of chemical processes: a review. Comput. Chem. Eng. 28, 2109?2129 (2004).

8. X. Lin, S.L. Janak, & C.A. Floudas. A new robust optimization approach for scheduling under uncertainty: 1. bounded uncertainty. Comput. Chem. Eng. 28, 1069?1085 (2004).

9. X. Lin, E.D. Chajakis, & C.A. Floudas. Scheduling of tanker lightering via a novel continuous-time optimization framework. Ind. Eng. Chem. Res. 42, 4441?4451 (2003).

10. X. Lin & C.A. Floudas. A novel continuous-time modeling and optimization framework for well platform planning problems. Optim. Eng. 4, 65?95 (2003).

11. X. Lin, C.A. Floudas, S. Modi, & N.M. Juhasz. Continuous-time optimization approach for medium-range production scheduling of a multi-product batch plant. Ind. Eng. Chem. Res. 41, 3884?3906 (2002).

12. X. Lin & C.A. Floudas. Design, synthesis and scheduling of multipurpose batch plants via an effective continuous-time formulation. Comput. Chem. Eng. 25, 665?674 (2001).