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TBacteria that eat, reproduce and breathe in small plastic plates sprinkled with nutrient broth in Jason Chin's laboratory in the suburbs of London look pretty ordinary, but they differ fundamentally from any other living being on earth, mushrooms and avocados with tulips, robins, and elephants. They use a different genetic code – yet these artificial microbes are doing well.
In fact, these Escherichia coli have the most "recoded" genome ever created, said Chin and his colleagues at the British laboratory of molecular biology at the Medical Research Council in Cambridge, in Nature. "This is a major step," said Harvard biologist George Church, who did not participate in the new study. Here's what you need to know about what he and other scientists call a historic feat in synthetic biology.
What is "synthetic" in this genome?
All. It is the largest genome ever created by bringing together DNA blocks that scientists have ordered from a supplier. This is called "writing" a genome, which the scientists in the GP-Write project are trying to do. ("Read" a genome is what the human genome project did – determine the sequence of its millions or billions of DNA letters, or bases.)
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In 2010, genetic pioneer Craig Venter and his colleagues assembled the complete genome of the bacterium Mycoplasma mycoides in this way, and scientists with GP-Write synthesized 2 of the 16 chromosomes that make up the genome of a single strain of Baker's yeast. But the genome of Mycoplasma has only 1.08 million base pairs and yeast chromosomes less than 1 million. E. coli is 4 million. Chin cut it into 37 fragments and synthesized them, a process he called (of course) Genesis.
What is the recoding?
Basically, change the genetic dictionary. Each organism on Earth uses the same 64 codons (combinations of three letters of DNA A, T, C and G) to specify the amino acids entering the proteins it makes. TCA, for example, specifies serine, which means "extract this amino acid from the cell soup and attach it to the protein made by the cell." AAG specifies lysine. TAA means to stop adding amino acids to the growing protein. But AGT also means serine, just like AGC, TCT, TCC and TCG. If nature were effective, it would use 20 codons for 20 amino acids, plus one for "stop". Recoders correct redundant codons and assign new functions to them.
How did Chin get the recoding?
He and his team systematically replaced each occurrence of the serine codon TCG with AGC, each TCA (also serine) with AGT, and each TAG (stop) with TAA, for a total of 18,214 replacements. "There are many ways to recode a genome, but many of them are problematic: the cell is dying," said Chin. For example, supposedly synonymous codons nevertheless produce slightly different amounts of protein and sometimes make unexpectedly-sensitive proteins that kill the cell. Chin discovered a recoding scheme that allowed his E. coli to stay alive despite using 59 codons instead of 61 to make the 20 amino acids of nature, and two codons instead of three to stop.
"They created a strain that does not use three of the codons that the rest of nature," said Tom Ellis, expert in synthetic biology at Imperial College London, who reviewed the document for Nature. "Life is still possible without all the constituent elements of nature." Chin calls the creation Syn61, for the number of codons used.
How unprecedented is it?
Synthetic biology has become a gaga for recoding. In 2013, scientists led by Church replaced the 321 UAG stop codons from E. UAA-stained, thus creating organisms surviving only by 63 codons, but not by genome synthesis. Three years later, Church's laboratory went one step further by replacing seven redundant codons with their synonyms, but in only a fraction of the E. coli genome it is not Syn57. Syn61 pushes recoding further than ever, building on Chin's 2016 research to identify the recoding patterns it would use for the current job. With three codons dropped in an entire genome, it performs hundreds of times more changes than any previous genome recoding.
Why is this a big problem?
"Recoding challenges the formula of life," said Ellis. "By recoding a genome, you can push the envelope of what nature has given us and see if you can do it differently."
But what practical reason is there for doing this?
By releasing, for example, the TCG and entrusting its work to the AGC, scientists could assign it a new function: encode for one of hundreds of amino acids beyond 20 acids amino acids transformed into proteins. With a recoded genome, a cell might be able to synthesize new enzymes and other proteins.
"Nature has given us all these enzymes that can do all these great things," said Ellis, ranging from cheese making to fruit juice extraction, producing biofuels and industrial chemicals, through the detection of biomarkers in medical tests. "It's from just 20 amino acids. Think of what you could do with 22 or more. There is a potential for manufacturing all kinds of new chemicals' for medicine, food production and the industry.
In addition, recoded genomes might be insensitive to viruses, as Church Syn61 said. This raises the possibility of recoding the genomes of the bacteria used to make everything from pharmaceuticals to foods, where viral infections cost the industry millions of dollars each year.
Did this new study do that?
No, but someone will do it. "The main breakthrough is that it can move forward," said Dr. Abhishek Chatterjee, a chemist at Boston College, who also reviewed Chin's document for Nature. He recently asked E. coli to incorporate unnatural amino acids into the proteins it makes, but not by Syn61-type recoding. This, says Chatterjee, "opens up completely new possibilities for the bacterial synthesis of biochemical substances." This also makes GP-Write's dreams more achievable: "We can see convergence on a standard strategy" for writing genomes, Church said, including for viral resistance. Chin's work, he said, "will greatly encourage the rest of the GP-Write community, which is working to make many organisms – industrial microbes, plants, animals and human cells – resistant to all thanks to this recoding approach ".
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