The biochemical language of life contains synonyms. Just as two words can have the same meaning, different combinations of "letters" in a genome. Last week, scientists have published a stripped-down, fully working version of Escherichia coli with some of the synonyms taken out (the good bacterium is often used as a model organism in basic research). The work was carried out by England's Medical Research Council Laboratory for Medical Biology and published in Nature.
Syn61, as this lab-made bacterium has been called, is a double milestone in synthetic biology, the quest to build life from scratch. First, it is the largest working genome ever built, coming in at four times the size of the previous record holder.
Second, it has been constructed using 61 rather than 64 codons (the combinations of letters that constitute the protein-generating instructions for organisms, including humans). Stripping out some of nature's synonyms opens up space for scientists to insert alternative instructions. In other words, creating a living organism with a compressed genetic code is a significant step on the path towards designer life forms.
The four building blocks, or bases, of DNA are popularly known as A, T, C and G (adenine, thymine, cytosine and guanine). They come in triplets called codons and there are 64 possible permutations (4x4x4), such as AGC and TCT. Oddly, several codons seem to serve the same purpose, suggesting that life has inbuilt redundancy. For example, the two codons above, plus another four, add up to six different recipes for making the same amino acid: serine.
Altogether, the 64 codons make a total of 20 amino acids that are variously assembled to make the protein needed to build and power life, with three codons acting as "stop" signs that halt protein manufacture.
The researchers in Cambridge wanted to see if they could come up with some of this overlap. They first recoded the E.coli genome on computer, as well as a "find and replace" function on a text file. They replace some codons with their apparent equivalents – a task that entailed more than 18,000 substitutions. Three codons were eliminated, resulting in the recipe for a 61-codon genome.
The researchers then assembled this genome using off-the-shelf chemicals. To test its viability, the lab-spun genome which is broken into several fragments and inserted into naturally occurring E. coli. These synthetic fragments, designed to be used in a natural way, were then recombined to produce E. coli with wholly synthetic DNA. The patchwork creation grows more slowly than its wild cousin but is broadly comparable.
Jason Chin, who led the two-year effort, described the breakthrough as "unfreezing the code". It is a reference to the late Francis Crick, the co-discoverer of DNA, who once described the ubiquity of three-letter codons in terrestrial life as a "frozen accident" of evolution. A Harvard University team is currently attempting to make a 57-codon genome.
If it can be recoded, then it can be repurposed – to make biofuels, better medicines, even to create pollution-eating bacteria. This is the goal that drives Craig Venter, the American geneticist who is now a pivotal figure in synthetic biology. So it's trying to reduce life to its bare biological essentials. In 2016, just 473 genes, the smallest genome of any known, succeeded in becoming independent. Even this extreme minimalism was carried out by mystery: it was unclear exactly what 149 of these genes did.
Reconstructing life – which broadly means investing lab-created organisms with the means to grow, reproduce and evolve – is technically tricky but raises weighty ethical, legal and social issues. Genome Project-Write, an independent non-profit effort launched in 2016 to synthesize a human genome.
For some, writing a human genome is the natural follow-up to reading it. The dividends of a project, according to its champions, include being able to grow. But many are wary of such technology being misused, perhaps to create human life in a new way.
It was once easy to dismiss such fears – until the disgraced scientist He Jiankui came to light. His creation of two genome-edited babies last year that happened occasionally do the unthinkable. Together, genome-editing and synthetic biology offer us the power to amend, and even rewrite, the book of life. We are still to have a meaningful public conversation on how far we want to exercise it.
The writer is a science commentator