B.S. Organic Chemistry, Peking University
M.S. Physical Chemistry, Peking University
Ph.D. Bioorganic Chemistry, University of California, Berkeley
Postdoc Pharmacology, University of California, San Diego
Cells use a limited number of molecular building blocks to achieve an amazing variety of functions for life needs. Understanding, utilizing, and enhancing such capabilities depend on how at will we are able to manipulate molecules inside cells. Our laboratory is interested in developing new strategies for molecular evolution and molecular imaging. These new methods will be applied to study cellular functions and to generate new biological activities. We combine chemistry, biochemistry, molecular biology and fluorescence techniques to achieve these goals.
"We are trying to expand the genetic code and insert artificial
amino acids into proteins in mammalian cells and multicellular
organisms, which provides novel tools to address questions that
are insurmountable with conventional means. We may also use
these amino acids to build new proteins as novel therapeutics."
Cells provide a dazzling variety of functions
that cover all of our body's needs, yet
they make do with a very limited number of
molecular building blocks. With few exceptions,
all known forms of life use the same
common 20 amino acids—and only those
20—to make all the proteins necessary to
keep organisms as diverse as humans, earthworms,
tiny daisies and giant sequoias alive.
During protein synthesis, amino acids are
brought out one by one by molecules known
as transfer RNAs (tRNAs) and added to the
growing protein chain according to the instructions
spelled out in the body's genes.
This continues until a stop codon—for which
no corresponding tRNA exists—lets everybody
know that this particular job is done.
By generating a new tRNA to recognize the
stop signal, novel amino acids can be attached
to this tRNA and inserted into any
protein, potentially generating new functions
for the protein. However, stop codons also
are naturally recognized by proteins called
release factors to terminate protein translation,
which results in competition between
the new tRNA and the release factor. The
efficiency for inserting novel amino acids is
often less than 10 percent, and it is extremely
difficult to put them at multiple
places in a protein. These problems have
prevented people from creating new protein
properties by harnessing the power of the
novel amino acids.
Release factors have been thought to be
essential for the life of bacteria since the
1980s, but Wang and his team recently
discovered that one release factor could
be removed from Escherichia coli, a workhorse
bacterium for protein expression.
They created multiple new E. coli strains,
which are able to insert new amino acids
at the stop signal with an efficiency of 99
percent, close to that of natural amino acids.
In addition, without the competition of the
release factor, these new bacteria now allow
the novel amino acid to be simultaneously
inserted at multiple places, which was not
feasible before with any other organisms.
This work introduces the possibility of exploiting
novel amino acids to generate new
biological functions for therapeutic or industrial
Awards and Honors
- NIH Director's New Innovator Award, 2008
- Basil O'Connor Starter Scholar, 2008
- New Faculty Award, California Institute for Regenerative Medicine, 2008
- Career Development Award, Ray Thomas Edwards Foundation, 2007
- Searle Scholar, 2006
- Beckman Young Investigator, 2006
- Top Young Innovator, MIT Technology Review TR100, 2004
- San Diego BioPharma Award, Sino-American Biotechnology & Pharmaceutical Professional Association and American Chemical Society, San Diego Chapter, 2004
- Young Scientist Award (Grand Prize) by Amersham Biosciences and the Journal Science, American Association for the Advancement of Science, 2003
- Merck Fellow of the Damon Runyon Cancer Research Foundation, 2003-2005
- Collegiate Inventor (Grand Prize), National Inventors Hall of Fame, 2002
Coin, I., Katritch, V., Sun, T., Xiang, Z., Siu, F.Y., Beyermann, M., Stevens, R.C. and Wang, L.* Genetically Encoded Chemical Probes in Cells Reveal the Binding Path of Urocortin-I to CRF Class B GPCR. Cell Link
Kang, J., Kawaguchi, D., Coin, I., Xiang, Z., O'Leary, D.D.M., Slesinger, P.A., and Wang, L.* In vivo Expression of a Light-activatable Potassium Channel Using Unnatural Amino Acids. Neuron 80, 358-370 (2013). PubMed
Xiang, Z., Ren, H., Hu, Y.S., Coin, I., Wei, J., Cang, H., and Wang, L.* Adding an Unnatural Covalent Bond to Proteins through Proximity-enhanced Bioreactivity. Nat. Methods 10, 885-888 (2013). PubMed
Johnson, D.B., Wang, C., Xu, J., Schultz, M.D., Schmitz, R.J., Ecker, J.R., Wang, L.* Release Factor One is Nonessential in Escherichia coli. ACS Chem. Biol. 7, 1337-1344 (2012). PubMed
Parrish, A.R., She, X., Xiang, Z., Coin, I., Shen, Z., Briggs, S.P., Dillin, A., Wang, L.* Expanding the Genetic Code of Caenorhabditis elegans Using Bacterial Aminoacyl-tRNA Synthetase/tRNA Pairs. ACS Chem. Biol. 7, 1292-1302 (2012). PubMed
Johnson, D. B., Xu, J., Shen, Z., Takimoto, J. K., Schultz, M. D., Schmitz, R. J., Xiang, Z., Ecker, J. R., Briggs, S. P. and Wang, L.* RF1 knockout allows ribosomal incorporation of unnatural amino acids at multiple sites. Nat. Chem. Biol. 7, 779-786 (2011). PubMed
Lacey, V. K., Parrish, A. R., Han, S., Shen, Z., Briggs, S. P., Ma, Y. and Wang, L.* A fluorescent reporter of the phosphorylation status of the substrate protein STAT3. Angew. Chem. Int. Ed. Engl. 50, 8692-8696 (2011). (Selected as a HOT paper by Editors). PubMed
Coin, I., Perrin, M. H., Vale, W. W. and Wang, L.* Photo-cross-linkers incorporated into G-protein-coupled receptors in mammalian cells: a ligand comparison. Angew. Chem. Int. Ed. Engl. 50, 8077-8081 (2011). (Selected as a VIP - Very Important Paper by referees). PubMed
Shen, B., Xiang, Z., Miller, B., Louie, G., Wang, W., Noel, J. P., Gage, F. H. and Wang, L.* Genetically encoding unnatural amino acids in neural stem cells and optically reporting voltage-sensitive domain changes in differentiated neurons. Stem Cells 29, 1231-1240 (2011). PubMed
Takimoto, J. K., Dellas, N., Noel, J. P. and Wang, L.* Stereochemical basis for engineered pyrrolysyl-tRNA synthetase and the efficient in vivo incorporation of structurally divergent non-native amino acids. ACS Chem. Biol. 6, 733-743 (2011). PubMed
Johnson, D. B. and Wang, L.* Imprints of the genetic code in the ribosome. Proc. Natl. Acad. Sci. U. S. A. 107, 8298-8303 (2010). (Selected as Editors’ Choice of Science, 328, 407, 2010). PubMed
Wang, Q., Parrish, A. R. and Wang, L.* Expanding the genetic code for biological studies. Chem. Biol. 16, 323-336 (2009). PubMed
Wang, Q. and Wang, L.* New methods enabling efficient incorporation of unnatural amino acids in yeast. J. Am. Chem. Soc. 130, 6066-6067 (2008). PubMed
Wang, W., Takimoto, J. K., Louie, G. V., Baiga, T. J., Noel, J. P., Lee, K. F., Slesinger, P. A. and Wang, L.* Genetically encoding unnatural amino acids for cellular and neuronal studies. Nat. Neurosci. 10, 1063-1072 (2007). PubMed
Wang, L.* and Tsien, R. Y. Evolving proteins in mammalian cells using somatic hypermutation. Nat. Protoc. 1, 1346-1350 (2006). PubMed
Wang, L. and Schultz, P. G. Expanding the Genetic Code. Angewandte Chemie International Edition, Invited Review, 2005, 44, 34-66. Download this article.
Wang, L., Jackson, W.C., Steinbach, P.A. and Tsien, R.Y. Evolution of New Nonantibody Proteins via Iterative Somatic Hypermutation. Proceedings of the National Academy of Sciences U.S.A. 2004, 101, 16745-16749. (Selected as News of the Week of Science, 2004, 306, 1457 and Research Highlights of Nature Methods, 2005, 2, 87). Download this article.
Wang, L. Amersham Biosciences and Science Prize for Young Scientists Essay "Expanding the Genetic Code" Science, 2003, 302, 584-585. Download this article.
Wang, L., Xie, J., Deniz, A. and Schultz, P. G. Unnatural Amino Acid Mutagenesis of Green Fluorescent Protein. Journal of Organic Chemistry 2003, 68, 174-176. Download this article.
Wang, L., Zhang, Z., Brock, A. and Schultz, P. G. Addition of the Keto Functional Group to the Genetic Code of Escherichia coli. Proceedings of the National Academy of Sciences U.S.A. 2003, 100, 56-61. (Selected as Editors' Choice of Science, 2003, 299, 1283). Download this article.
Wang, L., Brock, A. and Schultz, P. G. Adding L-3-(2-Naphthyl)alanine to the Genetic Code of E. coli. Journal of the American Chemical Society 2002, 124, 1836-1837. Download this article.
Wang, L. and Schultz, P. G. Expanding the Genetic Code. Chemical Communications Feature Article, 2002, 1-11. Download this article.
Wang, L., Brock, A., Herberich, B. and Schultz, P. G. Expanding the Genetic Code of Escherichia coli. Science 2001, 292, 498-500. Download this article.
Wang, L. and Schultz, P.G. A General Approach for the Generation of Orthogonal tRNAs. Chemistry and Biology, 2001, 8, 883-90. Download this article.
Wang, L., Magliery, T. J., Liu, D. R. and Schultz, P. G. A New Functional Suppressor tRNA/Aminoacyl-tRNA Synthetase Pair for the in vivo Incorporation of Unnatural Amino Acids into Proteins. Journal of the American Chemical Society 2000, 122, 5010-1. Download this article.
Salk News Releases
- Salk scientists crack riddle of important drug target, December 2, 2013
- Salk scientists expand the genetic code of mammals to control protein activity in neurons with light , October 16, 2013
- Salk scientists add new bond to protein engineering toolbox, August 5, 2013
- Salk Institute announces faculty promotions, April 2, 2012
- Bionic bacteria may help fight disease and global warming, September 22, 2011
- Salk researchers develop method to map cell receptor that regulates stress, July 19, 2011
- Unnatural" chemical allows Salk researchers to watch protein action in brain cells, July 5, 2011
- The Pre-History of Life: elegantly simple organizing principles seen in ribosomes, April 12, 2010
- Salk Investigator Lei Wang Receives NIH New Innovator Award, September 22, 2008
- Salk stem cell researchers receive New Faculty Awards, December 12, 2007
- Doing nature one better: Expanding the genetic code in living mammalian cells, July 2, 2007
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