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Synthorx Makes Proteins Using Expanded Alphabet of Synthetic DNA

Xconomy San Diego — 

A synthetic biology startup that grabbed headlines last year by inserting synthesized DNA in bacteria—and getting it to replicate—said yesterday it has taken its technology a step further—engineering the bacteria to make proteins that don’t exist in nature.

The advance announced by San Diego-based Synthorx has not yet been reported in a scientific journal, as the company plans to keep some aspects of its work secret. But if the results hold up, the process pioneered by Synthorx could open the way to important new methods for producing an enormously diverse range of biologic products, including antibody drugs for cancer, vaccines, and both large and small protein therapeutics.

“You can literally make millions of proteins on a daily basis,” Synthorx CEO Court Turner told me yesterday afternoon.

Using synthetic DNA to make proteins is an unprecedented advance because the technology can incorporate multiple and different amino acids into proteins—and do it in a robust and scalable way, Turner said.

Synthorx is now poised to produce proteins that include scores of amino acids that don’t exist in nature. The company intends to use the technology to develop its own internal drug discovery pipeline, and to seek partnerships with big biotech and pharmaceutical companies that can use the technology to expand and diversify their own drug discovery and development processes.

Turner, who does double duty as a venture partner with San Diego’s Avalon Ventures, helped found Synthorx last year on technology developed in the lab of Floyd Romesberg of The Scripps Research Institute. Avalon joined with San Diego’s Correlation Ventures to make an undisclosed seed-stage investment in Synthorx.

The startup now has eight full-time employees, which will expand to 10 or 12 by mid-2016, and has enough cash to operate well into 2017, Turner said.

In landmark research published last year in the journal Nature, Romesberg’s team created two synthetic nucleotides dubbed X and Y (d5SICSTP and dNaMTP), and successfully inserted the unnatural base pair in DNA, which normally consists of four nucleotides (A,C, T, and G). The team then coaxed E. coli bacteria containing the synthetic DNA (with six nucleotides—A,C,T, G, X, and Y) to successfully replicate with no changes in its synthesized DNA.

Synthorx says the integration of the X and Y synthetic nucleotides with DNA significantly expands the genetic alphabet, and promises to allow for site-specific incorporation of multiple, different novel amino acids into a single protein.

More letters in the genetic alphabet makes for more possible codons—the three letters that link to a particular amino acid building block. Synthorx said last year that its technology made it theoretically possible to use the 20 existing amino acids with as many as 152 synthetic amino acids to assemble proteins that would be unknown in nature and have a host of new functions.

The work begun in Romesberg’s lab subsequently moved to Synthorx, where scientists used the synthesized DNA and the cellular machinery that assembles proteins from amino acids to make full-length and functional proteins out of amino acids that don’t exist in nature.

Asked if the process is analogous to the development of combinatorial chemistry in the 1980s and ’90s, Romesberg replied in an e-mail, “Combichem promised to identify compounds with new structures but composed of the same types of groups.

“The technology that Synthorx and my lab are developing promises to add entirely new types of groups to proteins (which are of course now validated therapeutics) which should not just optimize already existing activities (or arrangements of atoms like combinatorial chemistry does) but to add completely new functions.”