Serine? So last century. Valine? Over it. Glycine? You’ve got to be kidding me.

Those chemicals are part of the 20 amino acids that are typically incorporated into proteins. That means they have a dedicated place in what's called the genetic code, which translates between the bases of DNA to the amino acids of proteins.

Granted, the genetic code has enabled the entire diversity and complexity of life on Earth, from E. coli to T. rex. But still, researchers are starting to find this kind of limiting. Life has evolved ways of using more than 140 amino acids in proteins; and once we start tinkering with the things, we can make scads more. Just because evolution has done so doesn't mean we need to rely on only these 20 old boring ones. What follows is a look at how and why we want to engineer artificial amino acids into cells and living organisms.

Tweaking translation

Transfer RNAs (tRNAs) act as the bridge between DNA and amino acids—the DNA-based directions for how to make a protein and the protein itself. Each set of three bases in DNA can designate one of the 20 canonical amino acids. The tRNAs “read” this genetic triplet and deliver the designated amino acid onto the growing protein. So in order to add a new, artificial amino acid to proteins, researchers have had to engineer—or in some rare cases, find in microbes—a tRNA molecule that will put it into proteins when presented with a specific DNA code.

Usually, the DNA triplet used is not one that already designates an amino acid. Rather, it is one that signals the cell to stop adding amino acids to a protein. Most organisms have three of these stop codes and, with a bit of engineering, can get by with two. Scientists can then put this stop sequence into the middle of genes along with a tRNA that responds to it. When the gene is translated into protein, the tRNA will add an artificial amino acid into the elongating protein chain. Of course, the scientists must supply the cell with the artificial amino acid as well.

Using this strategy, artificial amino acids have been incorporated into plants and laboratory animals including roundworms, fruit flies, and mice. Mostly, it has been used to study the proteins themselves.

Primarily, the technique is used to label specific proteins to understand where and when the protein is made. Other uses include generating proteins that remain linked to any proteins they interact with until the researchers (chemically) tell them to let go. This lets the researchers find protein linkages that might otherwise be too fleeting to detect. It's also possible to use artificial amino acids to block a protein's function, again in a manner that can be lifted at will. This ability to turn protein function on and off in a chosen cell type and at a chosen time can help elucidate protein function and might also be exploited therapeutically.

It's also possible to track how cells manage their proteins. Many proteins are activated, shut down, or targeted for destruction by having small chemicals added to them (things like phosphates, acetyl groups, or others). The artificial amino acid approach allows researchers to slip in amino acids that come pre-modified in some way. Controlling when and where these modifications occur can allow us to better figure out what happens to a protein after it's modified.

At the other extreme, you can try something radically different. Other researchers are adding in amino acids “with new chemical structures and properties that has allowed the evolution of proteins with novel or enhanced function.”

To the clinic?

This work has stayed in the realm of basic research, but clinical and even commercial opportunities abound. Modifying antibodies or other immunoactive molecules could allow doctors to turn on and off their activity at the optimal times and places. An artificial amino acid can be inserted into a target protein to enhance the specificity and therefore efficacy of the drug targeting it.

Generating pathogens that are dependent on artificial amino acids can provide a new way of making attenuated bugs for vaccines—after all, they can’t reproduce in cells that lack the requisite artificial tRNAs.

Since all tRNAs do is add subunits onto growing chains, some speculate that they can one day be harnessed to move beyond linking amino acids to make proteins. Depending on the building blocks we give them, they can perhaps be used to make all different types of polymers.

An alternate way to get artificial amino acids into proteins is to alter the genetic code read by the tRNA molecules. Since there are four different bases used by genes (A, T, C, and G), there are 64 triplets currently used to encode the 20 canonical amino acids. These 64 are all that researchers can mess with. But they have made tRNAs that can recognize groups of four nucleotides instead of three, giving them 256 discrete combinations. That means 256 possible artificial amino acids—or whatever molecules protein scientists dream up next—for bioengineers to play with.

Given that so many of the possible amino acids occur naturally, it's generally thought that life ended up settling on its list of 20 largely by accident. With our ability to modify genes, we're poised to greatly expand the list of what life can work with.

Nature, 2017. DOI: 10.1038/nature24031 (About DOIs).