Researchers from Cambridge have developed Syn57 – an artificial E. coli bacterium that uses only 57 codons out of 64. The development could lead to the production of artificial proteins, new drugs and better control of industrial bacteria.
What is the minimum genetic information needed to keep a bacterium alive? And can this information be used to benefit humans?
About a decade ago, Craig Venter – a geneticist, biochemist and businessman – announced that he had created “Artificial” bacteriaIt might be more accurate to say that Shunter and his team “recreated” the bacteria. Mycoplasma mycoides, which has an extremely small genome. They artificially synthesized the DNA of that bacterium, then implanted it into a bacterial cell without DNA. However, this DNA was almost indistinguishable from the original. Later, Venter and his collaborators created the The artificial bacteria It has the fewest number of genes necessary for life, at least as far as we know – 473 genes out of about 900 genes found in the natural genome of mycoplasma. However, the genetic code itself, by which the information in DNA is used to produce proteins, remains unchanged in these artificial bacteria.
Three bases, one acid
The genetic material, DNA, is built as a long chain of four molecules – nitrogenous bases – marked with the letters A, T, C and G. In contrast, the building blocks of proteins are twenty amino acids, also arranged in long chains. How can a language of only four letters encode twenty amino acids? In the 1960s, Marshal of Nuremberg Nirenberg and Heinrich Matthaei Decipher the genetic code. They used an RNA molecule, which is a copy of part of the DNA (one of the differences between RNA and DNA is that the base T is replaced by another base, called U) and is used in the cell as an intermediary molecule for creating proteins. In this way, they were able to show that three letters in DNA constitute a “codon,” and each codon signals the cell to add a specific amino acid to the chain. For example, the codon AUG indicates the amino acid methionine, the codon UUU indicates the amino acid phenylalanine, GAG indicates glutamate, and so on. Since there are four letters, the number of possible combinations is 64 (4 to the power of 3), much more than the 20 combinations required for the twenty amino acids used by living things. Indeed, it was found that some of the amino acids are specified by two to six different codons. In addition, there are three codons that mean “stop” – a signal to stop the construction of the amino acid chain that will become a protein. Each codon has an associated system in cells that is responsible for the translation of that codon.
With the exception of a few exceptions, which use 62 or 63 of the 64 codons, all living things on Earth use all 64 codons, but At different frequenciesThe amino acid isoleucine, for example, is encoded by three different codons. In E. coli, the codon AUU is used about 50 percent of the time, AUC about 39 percent, and AUA about 11 percent. In humans, however, the frequencies of use are 36 percent, 48 percent, and 16 percent, respectively.
These differences, which have been fixed in different organisms during evolution, affect the way proteins are translated. For example, if the codon is rare, there are also few molecules of the accompanying system for translating the codon, so it will take the cell longer to translate it, and the system may even get stuck. Therefore, when researchers produce human proteins in E. coli for research or industry, it is important to match the codon usage to that of the bacteria.
All proteins, minus codons
Is it possible to reduce the number of codons in the genome of a living creature without harming it?
Jason Chin and his research group at the MRC Research Institute in Cambridge, England, did just that. In a studyReleased In the journal Nature, they created an E. coli bacterium (E. coli) artificial. This is a bacterium with a much larger genome than that of mycoplasma, containing about 4,000 genes. The new artificial bacterium uses only 61 codons. The amino acid serine (Ser) has six different codons (see figure); the researchers replaced two of the six serine codons with one of the other four throughout the bacterium’s genome, so that there would be only four codons for serine in the bacterium. In addition, they replaced one of the “stop” codons with another “stop” codon. In total, the researchers replaced 18,214 codons.
How did the researchers make such large-scale genetic changes to the bacterium’s genome? Because of its vast size, it couldn’t be done using genetic engineering methods that take DNA and change it, each mutation individually. Instead, the researchers synthesized DNA chemically in a test tube (as Venter did in 2010), and included all the desired mutations in the sequence from the start. The E. coli genome consists of four million “letters” (four times the size of the Mycoplasma genome, which only has about a million letters). To produce this length artificially, the researchers had to assemble about 40 pieces, each with 100,000 letters—a considerable feat in itself, and a new record for the production of a long artificial genome.
Surprisingly, the artificial bacterium, Syn61, was very similar to the original bacterium. Its growth rate was 1.6 times slower, and the entire cell was slightly longer, but the composition of the proteins in the cell was almost the same. However, the researchers reported that more in-depth testing is needed to understand how reducing the number of codons affects the bacterium – for example, testing how it behaves under different growth conditions or examining its evolution (through experiments). Evolution in the laboratoryThe researchers also removed the accessory systems for the missing codons and showed that, unlike the original bacterium, the accessory systems are not essential for the syn61 bacterium, as expected – because without the codons they remain without a function.
Possible applications
This is not just pure biological research: it also has an applied purpose in the field of synthetic biology. Now that we can create bacteria with fewer than 64 codons, we can take advantage of the redundant codons and make them code for other, unnatural amino acids. Such uses have already been Tried before, in studies in which researchers have caused one of the “stop” codons to symbolize an unnatural amino acid, thus inserting it into essential proteins in the bacterium. Bacteria in which such a change has been made are completely dependent on an artificial nutritional supplement containing that amino acid, and will die if it is not given to them. This allows the population of bacteria to be controlled in industry without fear that they will “escape” and contaminate the environment. Such bacteria are also very useful for another reason: they are easy to protect against viruses that attack bacteria, and can cause damage to industries that use bacteria, such as the cheese and yogurt industries. If a bacterium is missing a codon or two – and also the entire system used to translate that codon – a virus that does use that codon and penetrates the bacterium will not be able to replicate, because the translation of its proteins will be blocked. George Church’s laboratory at Harvard Has already begun developing a bacterium with 57 codons, but so far only in 63 percent of the genome.
An even more exciting possibility is to let bacteria produce entirely new proteins containing some unnatural amino acids. Such new materials could be used to make medicines and food, fertilizers, pesticides, adhesives, building materials, textiles, and more.
And not just bacteria – researchers in the project “Save 2.0"Artificial chromosomes of baker's yeast are already being produced - a single-celled fungus used in the bread, beer and wine industries, and its genome includes about 12 million letters. It is not impossible that in the not-so-distant future yeast with completely artificial genomes will be produced, which could improve or enrich the food industry."
Will we be able to create artificial multicellular creatures in the future? Time will tell.
Update from September 2025
Six years after developing Syn61 – a bacterium that uses only 61 of the 64 codons of DNA – Qin's research group developed a bacterium with only 57 codons (Syn57), in a study Published in the journal ScienceThe new development is starting to fulfill Syn61's promise: Qin and other researchers have begun using the artificial bacterium to examine You Durability His work is on bacteriophages, viruses that infect bacteria. They are also testing whether the genetic modification can Prevent Transfer of genes, especially those that confer antibiotic resistance, from other bacteria. In addition, researchers are examining the production of New proteins Artificial, with amino acids different from normal, on the basis of which it will be possible develop Future medicines.
The article describing the development of Syn57 is largely technical, describing the design of the changes to the genetic code, the production, and the assembly of the genome using methods similar to those used to create Syn61. At the end of the article, the researchers briefly mention that the new bacterium reproduces four times slower than a normal bacterium, and that some of its genes are expressed differently than in a normal bacterium – but they do not discuss the significance of these changes. In the future, they intend to use Syn57 in a similar way to the uses already made of Syn61, but on a larger scale.
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Why does this slow down the rate of reproduction of the bacteria?