The code of life is easy. 4 genetic letters arranged in triplets—called codons—encode amino acids. These are the constructing blocks of proteins, the machinery that powers life.
However the genetic code is redundant. Several codons could make the identical amino acid. Is that this nature’s way of protecting the genome, or is it an evolutionary fluke?
Scientists studying synthetic bacteria can have a solution. In a technological tour de force, a team on the Medical Research Council Laboratory of Molecular Biology constructed living bacteria with multiple of those redundant DNA parts recoded—making it a posh synthetic creature with one among the strangest genomes ever engineered.
The team made 100,000 genetic changes, slashing the 64 codons universal to all life to simply 57.
“It’s sort of crazy that they were in a position to pull this off,” Yonatan Chemla, an artificial biologist at MIT who was not involved within the study, told the Latest 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 outcomes also lay the groundwork for genetic and medical discoveries. Parts of the synthetic genome could possibly be recoded to show the bacteria into tiny manufacturers that produce life-saving medications. And since they lack the genetic machinery viruses exploit during infections, the bacteria could possibly be proof against contamination.
Radical Rewrite
All living things use the identical 4 DNA letters—A, T, C, and G. The cell’s molecular machinery reads them in groups of three—triplets often called codons—because it translates them into different amino acids. In all, there are 64 codons. Sixty-one of those represent twenty different amino acids, and three give cells a “stop” signal that terminates the growing protein chain.
But the mathematics doesn’t add up. Some codons are redundant. For instance, TCG encodes the amino acid serine, but so do five other codons. This has led scientists to wonder: What happens if we do away with those extra codons—for instance, have only TCG represent serine—and reassign those now “empty” spots to other amino acids?
At first, this was not more than a fever dream. But due to the rise of highly efficient, reasonably priced gene-editing tools comparable to CRISPR, scientists have made regular headway. Nearly a decade ago, a Harvard team replaced seven codons with alternative (but synonymous) codons within the bacteria Escherichia coli, a typical workhorse within the lab that’s also widely utilized in biotechnology.
It was an amazing endeavor. E. Coli’s genome is roughly 4 million base pairs long, with codons scattered throughout, making it nearly not possible for gene editing tools to focus on them one after the other. As an alternative, the scientists made the tailored genome from scratch.
They took a “divide and conquer” approach, constructing the reprogrammed DNA in 55 fragments. But they weren’t in a position to piece those fragments together into functional bacteria.
Three years later, Jason Chin, the lead writer of the brand 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 within the natural world.
This was successful, however it wasn’t clear how much further scientists could go, wrote the team.
Meet Syn57
The brand new work took aim on the amino acids serine and alanine, each encoded by multiple codons. The team aimed to create living synthetic bacteria with seven codon changes: 4 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 could possibly affect how cells make the ultimate protein—for instance, slowing down protein production and eventually killing the bacteria. So, somewhat than recoding the whole genome directly, the team began small and monitored the bacteria’s health with each latest step.
They first tried multiple codon compression strategies on a small section of the E. Coli genome wealthy in genes needed for growth and survival. After pinpointing several “recoding schemes” that didn’t appear 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 many 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 might limit growth when altered.
“Mapping and fixing at each stage of the synthesis was often crucial to enabling the subsequent step of the synthesis,” wrote the team. These experiments helped catch faulty designs and led to “just in time” fixes that fine-tuned the whole synthetic genome—4 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 complete 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 speed up growth, they wrote.
A Synthetic Life Boom
Syn57 could soon have company. Last yr, 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 right 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 is also engineered to scour the environment for pollution or chomp up microplastics. Because they use a unique genetic dictionary, the synthetic creatures are unlikely to contaminate natural populations and wreak havoc on ecosystems.
The authors are actually trying to higher their creation by cleansing 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 ends in some shuttles without an amino acid passenger. This might confuse and disrupt cellular processes. Ridding the cells of redundant transfer RNAs—and potentially adding latest ones that shuttle latest synthetic amino acids—may lead to sturdier synthetic organisms with unusual biotechnological uses.
The outcomes also suggest that genetic redundancy could possibly be a sort of evolutionary accident, cemented in time as proteins became more complex in order to not disrupt them.
With synthetic biology, “you possibly can start exploring what life will tolerate,” said Nyerges.