My laboratory is interested in the related challenges of understanding the origin of life on the early earth, and the construction of artificial cellular life in the laboratory. Focusing on artificial life frees us to explore novel chemical systems, but what we learn from these systems helps us to understand possible pathways leading to the origin of life. Our basic design for an artificial cell involves the encapsulation of a spontaneously replicating nucleic acid, which acts as the genetic material, within a spontaneously replicating membrane boundary, which provides spatial localization. We use chemical synthesis to make nucleic acids with modified nucleobases and sugar-phosphate backbones. Our goal is generate a nucleic acid system that can replicate accurately and rapidly, without any enzymatic assistance. We have already developed a membrane vesicle system that allows for the repeated growth and division of the vesicles, without the involvement of any biochemical machinery. We are just beginning to do experiments in which we combine the nucleic and membrane systems, and we can already see the beginnings of nucleic acid replication within our membrane vesicles. Once we achieve repeated cycles of replication of the combined system, we expect to see evolutionary forces come into play, leading to the spontaneous emergence of nucleic acid sequences that contribute to the fitness of the artificial cell.
The other major project within my laboratory is the development of a new approach to drug discovery. Our goal is to modify the cellular translational apparatus to allow for the ribosomal translation of molecules that are chemically similar to natural products such as cyclosporin and vancomycin. Using a reconstituted peptide synthesis system, we can now generate cyclic peptides that incorporate a wide range of amino acid analogs. We are generating large libraries of such small molecules in an mRNA-displayed format, so that we can select for high affinity binders to biomedically interesting targets.
Subject areas for rotation projects:
- Explore prebiotic nucleic acid replication using a chemical model system.
- Explore the biophysics of our replicating vesicle system.
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References:
- Hanczyc MM, Fujikawa SM, Szostak JW. Experimental Models of Primitive Cellular Compartments: Encapsulation, Growth and Division. Science, 2003; 302:618-622.
- Chen IA, Roberts RW and Szostak JW. The Emergence of Competition Between Model Protocells. Science, 2004; 305:1474-1476.
- Josephson K, Hartman MCT, Szostak JW. Ribosomal Synthesis of Unnatural Peptides. J. Am. Chem. Soc., 2005; 127:11727-11735.
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