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Expanding the Genetic Code in Mammalian Cells

Salk researchers have developed a method to make mammalian cells crank out designer proteins by incorporating synthetic amino acids, a feat that suggests cells could make their own therapeutic proteins.

Lei Wang, assistant professor in the Chemical Biology and Proteomics Laboratory, and Paul Slesinger, associate professor in the Peptide Biology Laboratory, reported the method in Nature Neuroscience and tested it in a proof-of-principle experiment. Plants and animals construct protein chains from 20 naturally occurring links, or amino acids. Although the amino acid order differs depending on the protein, the 20 amino acids are invariant.

Using bits and pieces of the protein synthesis machinery borrowed from bacteria and yeast, Wang and Slesinger devised a way to make nerve cells insert an unusually large "ringer" amino acid into a test protein that forms a channel through the cell membrane.

Normally, that channel, which is a conduit for potassium ions, comes equipped with its own tethered "plug" to regulate ion flow. To test their strategy, the researchers manipulated nerve cells to place the bulky, artificial amino acid in the region where the protein plug should fit into the channel pore.

They observed that once in the membrane, the synthetic channel regulated the flow of ions very inefficiently, indicating that inclusion of the bulky amino acid had made the plug too big to fit through the pore.

Chemists can already make proteins containing synthetic amino acids in a test tube. Although bacterial cells have been coerced into manufacturing similarly engineered proteins, this is the first report of nerve cells being tricked into doing the chemistry themselves.

Coaxing mammalian cells–even high maintenance cells like nerve cells–into manufacturing proteins with novel properties will be extraordinarily useful for both basic and medical research, potentially leading to new ways of delivering proteins with unimagined activities to cells.