Some 3.5 billion years ago, life on Earth evolved to have just four “letters” in its genetic code. These letters are the DNA bases G, C, A and T—and they spell out the instructions for making proteins in every organism on Earth.
But scientists in a lab at The Scripps Research Institute (TSRI) have been working on something new. They’ve designed a bacterium with two unnatural bases, called X and Y, which could someday help them produce new molecules for medical therapies.
the researchers announced that their “semi-synthetic” strain of E. coli is the first to both contain the unnatural bases in its DNA and use the bases to instruct cells to make a new protein.
This is the first time ever a cell has translated a protein using something other than G, C, A or T.
The new research builds on the Romesberg Lab’s previous efforts to expand the limited “alphabet” of natural DNA. Until now all organisms use have used only the four DNA bases to code for 20 amino acids. With the addition of X and Y, an organism could code for up to 152 new amino acids. The researchers hope these amino acids could become building blocks for new medicines.
Synthorx, Inc., founded on research from the Romesberg Lab, is leading the effort to develop protein therapeutics based on X and Y.
Cells Can Decode New Bases to Make Protein
Romesberg and his team worked toward this breakthrough for 20 years. Their research took a huge step forward in 2014, when the team announced the creation of a semi-synthetic organism that could copy X and Y in its DNA. Earlier this year, the researchers also found that they could get bacteria to stably store the information and pass on the unnatural bases to daughter cells as they divide.
But just storing these bases isn’t enough. To really be useful, these bases need to be “read,” or transcribed, into RNA molecules and translated into proteins.
Romesberg and his colleagues achieved these important steps by embedding their unnatural bases in genes that also contained A, C, G and T. They found that within the semi-synthetic organism these genes could be successfully transcribed into RNA molecules also containing the unnatural bases, and that the cells could use these RNA molecules at their ribosomes to direct the incorporation of unnatural amino acids into proteins.
The protein produced in this process was a variant of green fluorescent protein (GFP), a naturally glowing marker often used in genetic experiments, which contained different unnatural amino acids incorporated at a selected site.