Protein Made by Synthetic Bacteria with Expanded DNA

Cells express green fluorescent protein encoded from artificial DNA (Bill Kiosses, Scripps Research Institute)

29 November 2017. An academic-industry lab team produced a synthetic protein from an engineered bacteria, with DNA modified to expand its number of chemical coding components. Researchers from Synthorx Inc. and Scripps Research Institute, both in La Jolla, California published their findings in today’s issue of the journal Nature (paid subscription required).

Synthorx is a 3 year-old company spun-off from the Scripps synthetic biology lab of Floyd Romesberg that studies protein chemistry. Romesberg is Synthorx’s scientific founder and continues on the company’s board.

Among the lab’s discoveries is a process for adding 2 more base-pairs, nucleic acid components configured into an organism’s genetic code, to DNA. Natural DNA has 4 base pairs, combinations of adenine (A), thymine (T), cytosine (C), and guanine (G). Amino acids are made from sequences of 3 of these components, which form the building blocks of proteins in organisms with instructions for cells.

Romesberg and colleagues found a way of adding 2 more base pairs, labeled X and Y, to DNA. With these extra base pairs, new kinds of proteins can be produced with “unnatural” chemistries for therapeutics that offer additional properties beyond the capability of proteins with a natural chemistry. The added base pairs make it possible to encode for up to 152 new amino acids for proteins with unique chemical characteristics that can be configured into therapies or other applications.

In the Nature paper, the Synthorx-Scripps team reports developing a new strain of E. coli bacteria, a microbe popularly associated with food poisoning, but in its benign forms is often used as a model organism in labs. The engineered E. coli was created with a plasmid, a circular DNA molecule found in bacteria, containing the X and Y base pairs. With this extra pair of components, the bacterial cell’s ribosome, or protein synthesis molecule, successfully decoded the DNA into new kinds of proteins.

The researchers tested the new E. coli strain’s ability to produce a new type of designed protein. The product in this case is a synthetic form of green fluorescent protein, a compound found naturally in jellyfish that illuminates by absorbing ultraviolet light. In labs, green fluorescent proteins are a workhorse compound often used to track the status of biological processes.

Scripps graduate student and first author Yorke Zhang says in an institute statement, “We were able to achieve purities of desired amino acid incorporation above 98 percent, which demonstrates how seamlessly our synthetic bases can be integrated into the natural processes for encoding and decoding genetic information.”

The new type of green fluorescent protein from the engineered E. coli served solely as a proof of concept, was not given any additional functions, and required the researchers to add the X and Y base pairs to the DNA. As a result, say the researchers, the engineered E. coli cannot exist outside the lab.

Laura Shawver, CEO of Synthorx, adds in a company statement, “Now that we have a semi-synthetic organism that can encode and translate expanded genetic information, we have an efficient system for the design and scale-up of novel protein therapeutics that impart improved pharmacological properties of biologics making them more efficacious, safer, and more convenient for patients.”

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• Field Tests of Genetically Modified Moths to Begin

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