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Developing the Expanded Genetic Code: G.C.A.T. Those four letters have been the world’s genetic vocabulary since the beginning of life on earth, that is, until Dr. Floyd Romesberg and his team created X and Y.

At TEDMED, Dr. Romesberg shares the science behind expanding the genetic alphabet from the four typical DNA nucleotides – A,T,G,C – to six that now include the synthetic nucleotides d5SICSTP and dNaMTP, which we call X and Y.

To help understand why this is important, you first must know that genetic information (DNA) is translated into functional molecules (proteins) via RNA (DNA -> RNA -> Proteins). Proteins carry out many of the functions of life. In addition, modified proteins are useful as therapeutics, such as insulin for diabetes and Herceptin to treat certain forms of breast cancer.

How a protein works is mostly determined by its shape, which is determined by the sequence of amino acids. Amino acids are the building blocks of proteins, and each one has a unique biochemical property.

To build each protein, DNA carries the instructions for how to string together different amino acids. DNA of the majority of organisms encodes the same 20 natural amino acids. However, to make new and better protein therapeutics, we need to incorporate different amino acids.

A wide diversity of synthetic amino acids can be created with useful characteristics that are not found in the 20 natural amino acids. These characteristics can be leveraged to improve delivery, potency, efficacy, selectivity and efficiency. Incorporating synthetic amino acids can create more diverse protein therapeutics.

According to Dr. Romesberg, the easiest way to introduce new synthetic amino acids into proteins is to increase the ability of DNA to code for more amino acids.  With the four DNA nucleotides, G.C.A.T., organisms can code for the 20 natural amino acids.  The two additional nucleotides, X and Y, now bumps that number to a possible 172 amino acids.

Through perseverance and more than 12 years of research, Dr. Romesberg and his team successfully incorporated X and Y into the genetic code of a single-celled organism.  The organism is able to maintain and replicate the new DNA nucleotides only if X and Y are provided in the nutrients, creating a simple safeguard.

With this scientific breakthrough in hand, Dr. Romesberg and Court Turner founded Synthorx, to advance the technology and create novel therapeutics to address many unmet medical needs.

Dr. Romesberg caught up with TEDMED in September 2016 to discuss what the last year has held for this new technology.  Read that interview here.

To learn more about the path to expanding the genetic alphabet, watch Dr. Romesberg’s TEDMED talk here.