February 1, 2010
Interschool Lab, Room 750 CEPSR
Speaker: Dr. Farren Isaacs, Harvard Medical School
Advances in high-throughput biology and biotechnology have led to an array of biological insights in medicine, agriculture and studies of diverse organisms. The breadth of diversity found among biological systems make them ideal to address global challenges, such as producing bio-based therapeutics, chemicals and energy. In addition to a thorough understanding of biological systems, achieving these goals requires safe and programmable control of biological systems. To date, scientists have been primarily using genetic engineering techniques similar to those developed 30 years ago to manipulate biological systems. Thus, foundational technologies that expand our ability to engineer cells are needed. To address this challenge, my research is focused on developing foundational cellular and biomolecular engineering technologies to understand and engineer biological systems. Specifically, I will discuss the development and application of small- and large-scale genome engineering methods for versatile genetic modification and evolution of cells: 1. MAGE: Multiplex Automated Genome Engineering (bp-Kbp+) and 2. GAMEC: Genome Assembly Mediated by Engineered Conjugation (Kbp-Mbp+). MAGE simultaneously targets many locations on the chromosome for modification in a single cell or across a population of cells, thus producing combinatorial genomic diversity. The MAGE technology was automated through the construction of prototype devices and applied to optimize the 1-deoxy-D-xylulose- 5-phosphate (DXP) biosynthesis pathway in E. coli to overproduce the industrially important isoprenoid lycopene. Twenty-four genetic components in the DXP pathway were modified simultaneously using a complex pool of synthetic DNA, creating over 4.3 billion combinatorial genomic variants per day. Variants with more than fivefold increase in lycopene production were isolated within 3 days, a significant improvement over existing metabolic engineering techniques. I have also applied MAGE to engineer strains of E. coli with a new genetic code. Specifically, I have replaced all 314 TAG stop codons with TAA synonymous stop codons across several strains using MAGE. To accumulate these codon changes into a single strain, I developed GAMEC to hierarchically assemble large genomic fragments from multiple strains, enabling rapid construction of recombinant genomes derived from 2+ genetically distinct strains. These changes to the genetic code allow us to construct safer and multi-virus resistant strains and enhance the incorporation of non-natural amino acids into proteins. My approach embraces engineering in the context of evolution by expediting the design and evolution of organisms with new and improved properties.
Farren Isaacs is a research fellow in the Department of Genetics at Harvard Medical School working on advanced genome engineering technologies with George Church. He received a B.S.E degree in Bioengineering from the University of Pennsylvania and obtained his M.S. and Ph.D. from the Biomedical Engineering Department and Bioinformatics Program at Boston University. He has studied dynamic expression of gene regulatory circuits through the construction of synthetic gene networks and pioneered the design and construction of synthetic RNA components capable of probing and programming cellular function. He develops enabling cellular engineering technologies with the ultimate goal of providing insight into biological systems and applying these insights to address global challenges in medicine, energy and the environment. He was recently selected as a "rising young star of science" by Genome Technology Magazine.