Hal Alper, Ph.D.
Principal Investigator
B.S., Chem. Eng., University of Maryland at College Park
Ph.D., Chem. Eng., Massachusetts Institute of Technology
Post-doc., Whitehead Institute
Post-doc., Shire Human Genetic Therapies
Research
The goal of metabolic and cellular engineering is to endow novel and useful properties to cellular systems. Recent advances in molecular biology and genetic engineering empower metabolic engineers with an increasing ability to create any desired cellular modification. The integration of these approaches with an ever-increasing database of knowledge about these cellular systems (due in part to genomic sequencing efforts) provides an unprecedented opportunity to engineer cellular systems. Our research group focuses on the integration and implementation of these tools and knowledge for the design, production, and elicitation of phenotypes relevant to biotechnological processes and medical interest.
Using a variety of host systems including microbial (eg. Escherichia coli), fungal (eg. yeast), and mammalian (eg. Chinese Hamster Ovary (CHO) cells), we seek to develop the necessary genetic tools and methodologies for creating industrially-relevant organisms for biomolecules, biofuels, and biopharmaceuticals. To accomplish this task, traditional pathway engineering will be utilized in conjunction with novel tools for introducing genetic control (such as global Transcription Machinery Engineering, promoter libraries, and gene mutagenesis).
Overall research goals:
· To develop new strategies and tools for the engineering and cultivation of cellular systems applicable to both eukaryotic and prokaryotic systems
· To develop suitable host strains (both mammalian and microbial) for the high level production of value-added products and bioactive molecules
· To understand and engineer complex cellular phenotypes, including disease states, in an effort to identify novel genetic targets
· To develop molecular biology tools which allow for both tunable and combinatorial control of gene expression and regulatory networks
· To develop strategies for engineering cellular systems through protein engineering and evolution
Publications
1. Hal Alper and Gregory Stephanopoulos, 2007. Global transcription machinery engineering: a new approach for improving cellular phenotype. Metab Eng. 9(3), 258-267.
2. Keith Tyo, Hal Alper, and Gregory Stephanopoulos, 2007. Expanding the metabolic engineering toolbox: more options to engineer cells. Trends Biotech. 25(3), 132-137.
3. Hal Alper, Joel Moxley, Elke Nevoigt, Gerald Fink, and Gregory Stephanopoulos, 2006. Engineering yeast transcription machinery for improved ethanol tolerance and production. Science 314(5805), 1565 - 1568.
4. Elke Nevoigt, Jessica Kohnke, Curt Fischer, Hal Alper, Ulf Stahl and Gregory Stephanopoulos, 2006. Engineering of promoter replacement cassettes for tuning gene expression in yeast. Appl Environ Microbiol 72(8), 5266-73.
5. Hal Alper, Kohei Miayaoku, and Gregory Stephanopoulos, 2006. Characterization of lycopene overproducing E. coli strains in high cell density fermentations. Appl Micro Biotech 72(5), 968-974.
6. Kyle Jensen, Hal Alper, Curt Fischer, and Gregory Stephanopoulos, 2006. Identifying functionally-important mutations from phenotypically diverse sequence data. Appl Environ Microbiol 72(5), 3696-3701
7. Hal Alper, Curt Fischer, Elke Nevoigt, and Gregory Stephanopoulos, 2005. Tuning Genetic Control through Promoter Engineering. PNAS. 102(36), 12678-12683.
8. Hal Alper, Kohei Miyaoku, and Gregory Stephanopoulos, 2005. Construction of lycopene-overproducing E. coli strains by combining systematic and combinatorial gene knockout targets. Nat Biotechnology. 23(5), 612 - 616.
9. Hal Alper, Yong-su Jin, J. Moxley, and G. Stephanopoulos, 2005. Identifying gene targets for the metabolic engineering of Escherichia coli. Metab Eng. 7(3), 155-164.
10. Yong-Su Jin, Hal Alper, Yea-Tyng Yang and Gregory Stephanopoulos, 2005. Improvement of xylose uptake and ethanol production in recombinant Saccharomyces cerevisiae through an inverse metabolic engineering approach. Appl Environ Microbiol 71(12), 8249-8256.
11. Hal Alper and Gregory Stephanopoulos, 2004. Metabolic Engineering Challenges in the Post-Genomic Era. Chemical Engineering Science. 59 (22/23), 5009-5017.
12. Gregory Stephanopoulos, Hal Alper, and Joel Moxley, 2004. Exploiting Biological Complexity for Strain Improvement through Systems Biology. Nat Biotechnology. 22(10), 1261-7.