At the heart of all life is a code. Our cells use it to turn the information in our DNA into proteins. So do maple trees. So do hammerhead sharks. So do shiitake mushrooms. Except for some minor variations, the genetic code is universal.
It’s also redundant. DNA can code for the same building block of proteins in more than one way. Researchers have long debated what purpose this redundancy serves — or whether it’s just an accident of history.
Thanks to advances in genetic engineering, they can now do more than just argue. Over the past decade, scientists have built microbes with smaller codes that lack some of that redundancy. A new study, published Thursday in the journal Science, describes a microbe with the most streamlined genetic code yet.
Remarkably, the engineered bacteria can run on an abridged code, making it clear that a full genetic code isn’t required for life.
“Life still works,” said Wesley Robertson, a synthetic biologist at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, and an author of the new study.
Our DNA is built from four different molecular building blocks, called bases: adenine, thymine, guanine and cytosine. A sequence of hundreds or thousands of these bases — known in brief as A, T, C and G — forms a gene. Our cells translate the sequence of bases in genes to make proteins.
To make the translation work, our cells read the bases three at a time, in units called codons. Each codon matches one of the 20 different amino acids that are available in the cell. It’s these amino acids that a cell strings together to form proteins.
A key feature of the genetic code is that more than one codon can encode the same amino acid. For instance, the triplet of bases TCT leads to the amino acid serine. But so do five other codons — TCC, TCA, TCG, AGT and AGC. All told, 61 different codons give rise to the 20 amino acids. Another three codons tell our cells when they have reached the end of the gene. With 64 codons in total, the genetic code is immensely redundant.
Scientists have puzzled over the bloated code of life ever since it came to light in the 1960s. With few exceptions, every species on Earth relies on the same 64 codons. Because the code is universal, scientists have speculated, there must be something essential about having so many ways to build a protein.
About a decade ago, scientists began testing this idea by building new, compressed genetic codes. Advances in DNA synthesis allowed them to construct genomes from scratch, eliminating some of the redundant codons to see whether cells could survive with a smaller code.
“You can start exploring what life will tolerate,” said Akos Nyerges, a synthetic biologist at Harvard Medical School who has been working on shrinking the genetic code. “We can finally test these alternative genetic codes.”
Dr. Robertson and his colleagues at the Medical Research Council have been working toward the same goal. Both teams have been tinkering with Escherichia coli, a species of bacteria that dwells in the human gut and has been intensively studied for more than a century. They picked out redundant codons to eliminate, hoping they wouldn’t harm the microbe in the process. Dr. Robertson and his colleagues, for instance, set out to reduce the six serine codons to just two.
These plans demand tremendous amounts of engineering. The genome of Escherichia coli is about four million bases long, and each type of codon appears in thousands of different places along its length. To carry out so many changes, the researchers must build entire genomes from scratch.
In 2019, the Medical Research Council team unveiled their first successful creation: a version of E. coli with only 61 codons, which they named Syn61. Its ability to survive without three codons encouraged them to whittle its genetic code down even further.
“We were motivated to see how far we could streamline the genetic code,” Dr. Robertson said.
He and his colleagues set out to create Syn57, a version of E. coli with only 57 codons. They entered a race with Dr. Nyerges and his colleagues at Harvard, who were already trying to reach that same goal.
For Syn61, the researchers had altered more than 18,000 codons in E. coli’s genome. To make Syn57, they would have to alter more than 100,000. They tested these changes by making small fragments of DNA and observing how well the microbe could read them.
Some changes caused no trouble, but others caused devastating harm. Bacteria have certain genes that overlap, for instance, and changing a codon in one can accidentally wreck the sequence of the other.
The scientists had to invent a lot of repairs to undo the damage, including separating overlapping pairs of genes to create two distinct stretches of DNA.
“We definitely went through these periods where we were like, ‘Well, will this be a dead end, or can we see this through?’” Dr. Robertson recalled.
Glitch by glitch, the researchers figured out how to fix the altered DNA. On Thursday, the researchers announced that they had succeeded: They had created Syn57.
“It’s kind of crazy that they were able to pull this off,” said Yonatan Chemla, a synthetic biologist at M.I.T. who was not involved in the study. “It’s a technically demanding tour de force.”
Meanwhile, at Harvard, Dr. Nyerges and his colleagues have encountered glitches of their own. “There’s a lot more in genomes than we thought,” he said. “We are still not great at designing biology.”
Last month, his team reported that they had assembled a 57-codon genome into seven pieces of DNA. They are now working on stitching them together into a single molecule. “We will definitely get there,” he said.
Syn57 is unquestionably alive, but just barely. E. coli typically takes an hour to double its population; Syn57 needs four hours. “It’s extremely feeble,” Dr. Chemla said.
Dr. Robertson and his colleagues are now tinkering with Syn57 to see if they can speed up its growth. If they succeed, other scientists might be able to engineer it to carry out useful jobs that ordinary microbes can’t.
Along with the 20 amino acids that our cells use to make proteins, chemists can create hundreds of others. It might be possible to reprogram Syn57 so that its seven missing codons encode unnatural amino acids. That would enable bacteria to make new kinds of drugs or other useful molecules.
Syn57 might also help scientists address the potential risks that could come if engineered microbes were released into the environment. Microbiologists have long investigated how microbes might eat plastic or detect pollutants in the ground. But bacteria trade genes with ease; a gene could escape from an engineered microbe and spread through the environment, potentially causing ecological harm.
Then again, that spread would become a threat only if other bacteria could read the engineered gene and make proteins from it. If the gene came from a microbe like Syn57, which used a different genetic code, it would be gibberish to natural microbes.
“We can then prevent the escape of information from our synthetic organism,” Dr. Robertson said.
Organisms like Syn57 are also allowing scientists to tackle the puzzle of the genetic code. In 1968, the Nobel-prize winning biologist Francis Crick sketched out two opposing hypotheses for why it is both redundant and universal.
One possibility was that the 64-codon genetic code had some hidden advantage over any other arrangement. When it evolved on the early Earth, natural selection favored it until it had outcompeted all others.
But Crick leaned toward a second explanation: The genetic code was largely the result of chance. He speculated that mutations caused certain codons to encode certain amino acids. As early life-forms expanded their genetic code, they could build more complex proteins. But evolution connected codons to amino acids at random.
Once the proteins became big and complex, the genetic code could evolve no further; any mutation that might change it would produce a lot of defective proteins. Crick called this scenario a “frozen accident.”
Dr. Robertson said that the ability of Syn57 to survive without seven codons led him to favor Crick’s frozen-accident theory. “This reveals that there is nothing fundamental about the universal genetic code,” he said.
Carl Zimmer covers news about science for The Times and writes the Origins column.
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