Scientists have created a living organism whose DNA is entirely human-made — perhaps a new form of life, experts said, and a milestone in the field of synthetic biology by researchers at the Medical Research Council Laboratory of Molecular Biology, who reported on Wednesday that they had rewritten the DNA of the bacteria Escherichia coli, producing a synthetic genome four times larger and far more complex than any previously created.“The achievement one day may lead to organisms that produce novel medicines or other valuable molecules, as living factories,” writes Carl Zimmer in Matter for the New York Times. “These synthetic bacteria also may offer clues as to how the genetic code arose in the early history of life.”
“It’s a landmark,” said Tom Ellis, director of the Center for Synthetic Biology at Imperial College London, who was not involved in the new study. “No one’s done anything like it in terms of size or in terms of number of changes before.”
Nine years ago, researchers built a synthetic genome that was one million base pairs long. The new E. coli genome, reported in the journal Nature, is four million base pairs long and had to be constructed with entirely new methods according to Jason Chin, a lead author of the study and currently a Program Leader at the Medical Research Council Laboratory of Molecular Biology (MRC-LMB), where he is also Head of the Center for Chemical & Synthetic Biology. He is also professor of Chemistry & Chemical Biology at the University of Cambridge.
The MRC-LMB lab says Chin has pioneered the development and application of methods for reprogramming the genetic code of living organisms. These approaches allow the site specific incorporation of designer unnatural amino acids, beyond the canonical 20, into proteins in diverse cells and organisms.
Chin, reports Zimmer, wanted to understand why all living things encode genetic information in the same baffling way: “The production of each amino acid in the cell is directed by three bases arranged in the DNA strand. Each of these trios is known as a codon. The codon TCT, for example, ensures that an amino acid called serine is attached to the end of a new protein.
“Since there are only 20 amino acids, you’d think the genome only needs 20 codons to make them. But the genetic code is full of redundancies, for reasons that no one understands. Amino acids are encoded by 61 codons, not 20. Production of serine, for example, is governed by six different codons. (Another three codons are called stop codons; they tell DNA where to stop construction of an amino acid.)”
Chin was intrigued by all this duplication and asks: “Were all these chunks of DNA essential to life? Because life universally uses 64 codons, we really didn’t have an answer.”
Creating an Organism that Could Shed Light on All the Duplication
Nature uses 64 codons to encode the synthesis of proteins from the genome, and chooses 1 sense codon—out of up to 6 synonyms—to encode each amino acid. Synonymous codon choice has diverse and important roles, and many synonymous substitutions are detrimental.
Chin’s lab demonstrated that the number of codons used to encode the canonical amino acids can be reduced, through the genome-wide substitution of target codons by defined synonyms. We create a variant of Escherichia coli with a four-megabase synthetic genome through a high-fidelity convergent total synthesis.
Their synthetic genome implements a defined recoding and refactoring scheme—with simple corrections at just seven positions—to replace every known occurrence of two sense codons and a stop codon in the genome. Thus, they recoded 18,214 codons to create an organism with a 61-codon genome; this organism uses 59 codons to encode the 20 amino acids, and enables the deletion of a previously essential transfer RNA.
Much to their relief, Zimmer reports the altered E. coli did not die. The bacteria grow more slowly than regular E. coli and develop longer, rod-shaped cells. But they are very much alive.
Chin hopes to build on this experiment by removing more codons and compressing the genetic code even further. He wants to see just how streamlined the genetic code can be while still supporting life.
Recoding DNA could also allow scientists to program engineered cells so that their genes won’t work if they escape into other species. “It creates a genetic firewall,” said Finn Stirling, a synthetic biologist at Harvard Medical School who was not involved in the new study.
Researchers are also interested in recoding life because it opens up the opportunity to make molecules with entirely new kinds of chemistry, writes Zimmer. “Beyond the 20 amino acids used by all living things, there are hundreds of other kinds. A compressed genetic code will free up codons that scientists can use to encode these new building blocks, making new proteins that carry out new tasks in the body.”
Image credit top of page: Burt Chan Artificial Life Award