How scientists are hacking the genetic code to give proteins new powers

For most of the history of life on Earth, genetic information has been carried in a code that specifies just 20 amino acids. Amino acids are the building blocks of proteins, which do most of the heavy lifting in the cell; their side-chains govern protein folding, interactions and chemical activities. By limiting the available side chains, nature effectively restricts the kinds of reaction that proteins can perform.

As a doctoral student in the 1980s, Peter Schultz found himself wondering why nature had restricted itself in this way — and set about trying to circumvent this limitation. Several years later, as a professor at the University of California, Berkeley, Schultz and his team managed to do so by tinkering with the machinery of protein synthesis. Although confined to a test tube, the work marked a key early success in efforts to hack the genetic code.

Since then, many researchers have followed in Schultz’s footsteps, tweaking the cellular apparatus for building proteins both to alter existing macromolecules and to create polymers from entirely new building blocks. The resulting molecules can be used in research and for the development of therapeutics and materials. But it’s been a hard slog, because protein synthesis is a crucial cellular function that cannot easily be changed.

“It’s a super-exciting field,” says Jason Chin, a synthetic and chemical biologist at the MRC Laboratory of Molecular Biology in Cambridge, UK. “Even from the beginning, I think it was clear that we were doing something really special.”

From vitro to vivo

To understand why, we have to consider how proteins are made (see ‘Protein hacking’).

During transcription, DNA instructions are copied into RNA, which is then translated into proteins in a molecular machine called a ribosome. Each triplet of bases in the RNA message (adenine, cytosine, guanine and uracil) represents a word, or codon, of the genetic code. There are 64 words in total — 61 that encode for amino acids and 3 that signal the ribosome to stop.

Amino acids are brought to the ribosome by transfer RNAs (tRNAs), each of which corresponds to a complementary codon. Enzymes known as aminoacyl-tRNA synthetases couple the tRNA to its cognate amino acid.

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