Salk Institute for Biological Studies


Lei  Wang

Lei Wang

Associate Professor
Chemical Biology and Proteomics Laboratory
Frederick B. Rentschler Developmental Chair



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 applications.

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