Department of Cell and Molecular Biology
The Skaggs Institute for Chemical Biology
Professor, Department of Cell and Molecular Biology
Faculty, Graduate Program
Directed Evolution of RNA and DNA Enzymes
Our research concerns the biochemistry of RNA and the development of novel RNA and DNA enzymes through in vitro evolution. Like their protein counterparts, nucleic acid enzymes assume a well-defined structure that is responsible for their catalytic activity. Unlike proteins, nucleic acids are genetic molecules that can be amplified and mutated in the test tube. Our laboratory has learned to exploit the dual role of nucleic acids as both catalyst and genetic molecule to develop RNA- and DNA-based evolving systems that operate entirely in vitro.
We regard Darwinian evolution as a chemical process that can be used to develop novel enzymes with desirable catalytic properties. A population of variant molecules is subjected to repeated rounds of selective amplification in the test tube. Only those individuals that perform a chosen catalytic task are amplified so that, through successive rounds, the population adapts to the task at hand. With the more advanced techniques that we have been developed, it is possible to carry out over 100 "generations" of test-tube evolution in a single day, employing a population of trillions of catalytic nucleic acids. This makes it possible to evolve molecules at a far more rapid pace compared with the rate at which whole organisms evolve in nature.
Our studies of RNA-based evolution are relevant to understanding the early history of life on Earth. It is believed that an RNA-based genetic system, termed the "RNA world", preceded the DNA and protein-based genetic system that has existed for the past 3.5 billion years. Our research aims to recapitulate the biochemistry of the RNA world in the laboratory. We are using in vitro evolution to explore the catalytic potential of RNA, and especially to develop RNA enzymes that have the ability to catalyze their own replication.
B.A., Biological Sciences, The University of Chicago, 1978
Ph.D., Neurosciences / Chemistry, University of California, San Diego, 1984
M.D., Medicine, University of California, San Diego, 1984
Medical licensure, State of California, 1985
Postdoctoral Fellow, The Salk Institute, 1985-1989
U.S. National Academy of Sciences Award in Molecular Biology, 1994
Pfizer Award in Enzyme Chemistry, 1995
Herbert W. Dickerman Award, 1997
Hans Sigrist Prize, 1997
Linnaeus Lecturer, Uppsala University, 2001
Member, U.S. National Academy of Sciences, 2001
H.C. Urey Award, 2005
Dannie Heineman Prize, 2009
U.S. National Academy of Sciences Miller Award, 2010
Member, American Academy of Arts and Sciences, 2012
Head of Faculty in Chemical Biology, Faculty of 1000
Technical Advisory Council, BP
Member, Institute of Medicine at the National Academy of Sciences, 2014
Director of the Genomics Institute of the Novartis Research Foundation (GNF)
For a complete list of publications: http://www.scripps.edu/joyce/publications.html
Sczepanski, J.T., Joyce G.F. A cross-chiral RNA polymerase ribozyme. Nature 515:440, 2014.
Lincoln, T.A., Joyce, G.F. Self-sustained replication of an RNA enzyme. Science 323:1229, 2009.
Voytek, S.B., Joyce, G.F. Niche partitioning in the coevolution of two distinct RNA enzymes. Proc. Natl. Acad. Sci. USA 106:7780, 2009.
Lam, B.J., Joyce, G.F. Autocatalytic aptazymes enable ligand-dependent exponential amplification of RNA. Nature Biotechnol. 27:288, 2009.
Paegel, B.P., Joyce, G.F. Darwinian evolution on a chip. PLoS Biol. 6:900, 2008.
Shih, W.M., Quispe, J.D., Joyce, G.F. A 1.7-kilobase DNA that folds into a nanoscale octahedron. Nature 427:619, 2004.
Joyce, G.F. The antiquity of RNA-based evolution. Nature 418:214, 2002.