Bacteria have been producing compounds for us since we discovered how to brew alcohol thousands of years ago. In 1982, we started giving them new genes, exponentially expanding the products they could make for our consumption. Recently, researchers in the US worked out a way to completely rewrite the genetic code of E. coli (1), a move that will no doubt usher in the next generation of bioproduction processes by removing the limits imposed by the natural biology of life.
1982. Famous for the release of the first commercial CD player, Michael Jackson’s record selling-album Thriller and the Falkland’s War. E.T. was in the cinemas and one-hit-wonder ‘Come on Eileen’ was on the radio. It was also the year that genetically engineered bacteria were approved for use in bioproduction, namely the manufacture of insulin. This was a significant milestone in the commercialisation of biotechnology, driving down the price of insulin, while increasing the uniformity and safety of the product (until then, insulin had been harvested from the pancreases of sheep and pigs).
We’ve come a long way since then. Genetic engineering is now carried out routinely in labs across the world and the access to an ever expanding list of fully sequenced genomes continues to provide new fodder for the craft. Indeed, the first ‘synthetic’ genome was recently created, built by piecing together bits of other genomes to create a completely unique bacterium. This month, researchers at MIT and Harvard took the evolution of synthetic genomes one step further, indentifying a way to rewrite the genome in a way that will allow us to build proteins that could never exist in nature (1).
Although the amount of proteins that can be created naturally is incredibly diverse, they are limited to a list of 20 fundamental building blocks, the naturally occurring amino acids. The genomes of every organism on this planet are written with this in mind, using specific motifs (known as codons) to code for each individual amino acid, which are strung together like beads on a string to create a protein. Although the code itself consists of 64 different codons, there is significant redundancy in the system, with a single amino acid often represented by more than one codon. In addition, there are several stop codons, which do not encode for an amino acid, instead acting like the full stop at the end of this sentence, instructing the cellular machinery that the protein is complete.
The researchers in the US took advantage of this redundancy to completely replace one of the stop codons in the E. coli genome with one of the other stop codons. The idea was to free this codon from its obligations as a stop codon, so it could be utilised for a completely different purpose.
Scientists could now take advantage of this ‘spare’ codon to create entirely new genes, capable of producing unique proteins containing an additional, user-specified amino acid. This might include those that have been designed by chemists to harbour favourable catalytic properties making them perfect for the rational manufacture of biological products.
Even more excitingly, the further development of this technique should make it possible to complete rewrite the genetic code, removing the redundancy and taking advantage of all 64 possible codons. As well as expanding the options available to biotechnologists, rewriting the genome of bio-productive bacteria would also likely render them insensitive to the sorts of viruses that have commonly plagued bio-manufacture processes.
There is still plenty of work to do before the new bacterial genomes are ready for use. For a start, the protein production machinery of the cell will need to be modified so that it can accurately take advantage of the repurposed codon. Once this has been achieved it will be possible to start assessing the cellular toxicity of editing the genetic code. Finally, safety issues concerning the custom editing of an organism genome will need to be assessed, in order to satisfy consumers and regulatory bodies that production using custom genomes is viable and acceptable.
Over the last 30 years genetically engineered bacteria have become a massively important production tool. If the new technique is a success, custom product design and batch production using microorganisms could become the method of choice for a wide range of applications… many of which are probably yet to be imagined.