Meet Syn57, the Most Stripped-Down Living Synthetic Bacteria Yet

The code of life is simple. Four genetic letters arranged in triplets—called codons—encode amino acids. These are the building blocks of proteins, the machinery that powers life.

But the genetic code is redundant. Several codons can make the same amino acid. Is this nature’s way of protecting the genome, or is it an evolutionary fluke?

Scientists studying synthetic bacteria may have an answer. In a technological tour de force, a team at the Medical Research Council Laboratory of Molecular Biology constructed living bacteria with multiple of these redundant DNA parts recoded—making it a complex synthetic creature with one of the strangest genomes ever engineered.

The team made 100,000 genetic changes, slashing the 64 codons universal to all life to just 57.

“It’s kind of crazy that they were able to pull this off,” Yonatan Chemla, a synthetic biologist at MIT who was not involved in the study, told the New York Times.

The bacteria grew and expanded like their natural counterparts, albeit at a slower rate, suggesting that life can still go on even with an abridged version of nature’s DNA playbook.

The results also lay the groundwork for genetic and medical discoveries. Parts of the synthetic genome could be recoded to turn the bacteria into tiny manufacturers that produce life-saving medications. And because they lack the genetic machinery viruses exploit during infections, the bacteria could be immune to contamination.

Radical Rewrite

All living things use the same four DNA letters—A, T, C, and G. The cell’s molecular machinery reads them in groups of three—triplets known as codons—as it translates them into different amino acids. In all, there are 64 codons. Sixty-one of these represent twenty different amino acids, and three give cells a “stop” signal that terminates the growing protein chain.

But the math doesn’t add up. Some codons are redundant. For example, TCG encodes the amino acid serine, but so do five other codons. This has led scientists to wonder: What happens if we get rid of those extra codons—for example, have only TCG represent serine—and reassign those now “empty” spots to other amino acids?

At first, this was no more than a fever dream. But thanks to the rise of highly efficient, affordable gene-editing tools such as CRISPR, scientists have made steady headway. Nearly a decade ago, a Harvard team replaced seven codons with alternative (but synonymous) codons in the bacteria Escherichia coli, a common workhorse in the lab that’s also widely used in biotechnology.

It was a tremendous endeavor. E. Coli’s genome is roughly four million base pairs long, with codons scattered throughout, making it nearly impossible for gene editing tools to target them one by one. Instead, the scientists made the tailored genome from scratch.

They took a “divide and conquer” approach, building the reprogrammed DNA in 55 fragments. But they weren’t able to piece those fragments together into functional bacteria.

Three years later, Jason Chin, the lead author of the new study, and colleagues engineered living bacteria that use only 61 codons to grow and reproduce. Chin’s team subsequently re-assigned multiple “empty” codons to make the bacteria invincible to all viruses, replacing over 18,000 codons with synthetic amino acids that don’t exist in the natural world.

This was a success, but it wasn’t clear how much further scientists could go, wrote the team.

Meet Syn57

The new work took aim at the amino acids serine and alanine, each encoded by multiple codons. The team aimed to create living synthetic bacteria with seven codon changes: Four for serine, two for alanine, and one for a stop codon.

Swapping genetic letters to make codon synonyms doesn’t change the resulting amino acid. But it can affect how cells make the final protein—for example, slowing down protein production and eventually killing the bacteria. So, rather than recoding the entire genome at once, the team started small and monitored the bacteria’s health with each new step.

They first tried multiple codon compression strategies on a small section of the E. Coli genome rich in genes needed for growth and survival. After pinpointing several “recoding schemes” that didn’t seem to harm the bacteria, they assembled synthetic DNA fragments that were roughly 100,000 letters in length and inserted them into multiple strains of E. Coli.

While most of the bacteria seemed relatively healthy, some didn’t survive or grew sluggishly. Digging deep into the cells’ genome, the team found curious bits of DNA that seemed resilient to reprogramming. Correlating the bacteria’s growth to which synthetic segments they’d added helped them pinpoint genetic regions that could limit growth when altered.

“Mapping and fixing at each stage of the synthesis was often crucial to enabling the next step of the synthesis,” wrote the team. These experiments helped catch faulty designs and led to “just in time” fixes that fine-tuned the entire synthetic genome—four million base pairs in total.

Years of tinkering and 100,000 edited codons later, Syn 57 emerged. The synthetic bacteria uses 55 codons to encode the full range of amino acids and two stop codons. The bacteria grew on a jelly-like surface and in a nutritious liquid, but four-times slower than their natural counterparts.

The team thinks further DNA tweaks can accelerate growth, they wrote.

A Synthetic Life Boom

Syn57 could soon have company. Last year, Akos Nyerges at Harvard Medical School and team engineered a 7-piece, 57-codon genetic scheme—described in a preprint—which they’re now stitching into a functional genome.

Meanwhile, Syn57 offers a whiteboard for further engineering. Scientists could assign synthetic amino acids to “empty” codons in Syn57’s genome so the cells produce protein-based medicines. The bacteria could also be engineered to scour the environment for pollution or chomp up microplastics. Because they use a different genetic dictionary, the synthetic creatures are unlikely to contaminate natural populations and wreak havoc on ecosystems.

The authors are now looking to better their creation by cleaning house. Molecular shuttles called transfer RNAs read natural codons, and based on each codon, they carry specific amino acids to the cell’s protein-making factory like cellular chauffeurs.

Compressing the genome results in some shuttles without an amino acid passenger. This could confuse and disrupt cellular processes. Ridding the cells of redundant transfer RNAs—and potentially adding new ones that shuttle new synthetic amino acids—could lead to sturdier synthetic organisms with unusual biotechnological uses.

The results also suggest that genetic redundancy could be a kind of evolutionary accident, cemented in time as proteins became more complex so as not to disrupt them.

With synthetic biology, “you can start exploring what life will tolerate,” said Nyerges.