Expanding the Boundaries of
Advanced Biomanufacturing Biology
 
Developing and applying synthetic biology and metabolic engineering to address challenges in advanced biomanufacturing, with a focus on sustainable manufacturing, nutrition and healthcare. Read More
 
 

  Our Research Program
Advanced biomanufacturing plays a pivotal role in the rapidly growing bioeconomy and creates a triple-bottom-line advantage that combines economic growth with public benefits and better lives for all citizens. The Metabolic Engineering Research Laboratory (MERL) seeks to develop and apply synthetic biology and metabolic engineering to address challenges in advanced biomanufacturing, with a focus on (1) Bio-based Chemicals, (2) Natural Products, and (3) Protein and Cell Based Therapeutics.
 
 
   

Bio-based Chemicals
We have engineered recombinant microorganisms to produce industrially important chemicals including n-butanol, adipic acid and 1-hexadecanol (1-3). However, their titer, yield and productivity are still relatively low. We will use novel genome-scale engineering approaches such as RNAi-assisted genome evolution (RAGE) (4,5) to optimize these engineered cellular factories for economical production and also improve their robustness under industrial settings. In addition, we will investigate the corresponding biological mechanisms for improved production and elucidate design principles.
   

Natural Products
The majority of existing antibacterial and anticancer drugs are natural products or their derivatives. However, the rate of discovering new natural products is diminishing despite the pressing need for new drugs (6,7). We will develop new strategies and tools to discover novel natural products with a focus on polyketides and terpenoids. In addition, we will engineer cellular factories to produce high-value natural products such as resveratrol and quercetin, two well-known neutraceuticals. Particularly, we will use RAGE to improve their production and combinatorial biosynthesis to generate new derivatives with improved neutraceutical properties.
   

Protein and Cell Based Therapeutics

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One major hurdle faced by existing cancer therapies is to selectively eliminate cancerous cells while minimizing adverse effects to healthy tissues (8). We will develop bacteria-based therapeutic platforms to selectively target, invade and kill cancerous cells. In addition, Chinese hamster ovary (CHO) cells are the most commonly used mammalian hosts for industrial production of recombinant protein therapeutics. However, the production levels are typically low. We will develop and apply new genome engineering tools based on TALEN and CRISPR (9-11) to engineer CHO cell lines with improved protein folding and expression machineries.
 

References
1. J. Du, Z. Shao, and H. Zhao. “Engineering a Microbial Factory for Synthesis of Value-added Products.” Journal of Industrial Microbiology and Biotechnology, 38, 873-890 (2011).
   
2. T. Si, Y. Luo, and H. Xiao, and H. Zhao. “Utilizing an Endogenous Pathway for 1-Butanol Production in Saccharomyces cerevisiae.” Metabolic Engineering, 22, 60-68 (2014). 
   
3. X. Feng, J. Lian, and H. Zhao. “Metabolic Engineering of Saccharomyces cerevisiae to Improve 1-Hexadecanol Production.” Metabolic Engineering, 27, 10–19 (2015). 
   
4. T. Si, Y. Luo, Z. Bao, and H. Zhao. “RNAi-Assisted Genome Evolution in Saccharomyces cerevisiae for Complex Phenotype Engineering.” ACS Synthetic Biology, DOI: 10.1021/sb500074a.
   
5. T. Si, H. Xiao, and H. Zhao. “Rapid Prototyping of Microbial Cell Factories via Genome-scale Engineering.” Biotechnology Advances, DOI:10.1016/j.biotechadv.2014.11.007. 
   
6. R. E. Cobb and H. Zhao. “Direct Cloning of Large Genomic Sequences.” Nature Biotechnology, 30, 405-406 (2012).
   
7. Y. Luo, H. Huang, J. Liang, M. Wang, L. Lu, Z. Shao, R.E. Cobb, and H. Zhao. “Activation and Characterization of a Cryptic Polycyclic Tetramate Macrolactam Biosynthetic Gene Cluster.” Nature Communications, 4: 2894 (2013). 
   
8. Z. Abil, X. Xiong, and H. Zhao. “Synthetic Biology for Therapeutic Applications.” Molecular Pharmaceutics, 12, 322−331 (2015). 
   
9. N. Sun and H. Zhao. “Transcription Activator-like Effector Nucleases (TALENs): A Highly Efficient and Versatile Tool for Genome Editing.” Biotechnology and Bioengineering, 110, 1811-1821 (2013).
   
10. N. Sun, J. Liang, Z. Abil, and H. Zhao. “Optimized TAL Effector Nucleases (TALENs) for Use in Treatment of Sickle Cell Disease.” Molecular Biosystems, 8, 1255 – 1263 (2012).
   
11. Z. Bao, H. Xiao, J. Liang, X. Xiong, N. Sun, T. Si, and H. Zhao.“A Homology Integrated CRISPR-Cas (HI-CRISPR) System for One-step Multi-gene Disruptions in Saccharomyces cerevisiae.” ACS Synthetic Biology, DOI: 10.1021/sb500255k