While scientists have previously modified the genetic code of organisms, they have never successfully recoded the genome in ways that fundamenally alter the organism’s biological function. But in the Oct. 18 issue of the journal Science, researchers at Yale and Harvard successfully recoded the genome of E. coli to expand viral resistance and allow researchers to more easily introduce new amino acids into the organism. The finding will help researchers modify proteins and improve the safety of biological organisms subject to viral infection, Yale professor of molecular, cellular and developmental biology and senior co-author Farren Isaacs said.
“We’re already seeing that we can link the viability of organisms to amino acids, and we’re starting to create new types of proteins and polymers that contain these new amino acids,” Isaacs said. “Over the next 10, 15, 20 years the production of new polymers could affect drug delivery, tissue engineering and the formation of new materials.”
The genetic code of most organisms consists of a sequence of 64 codons, triplets of nucleotides, that code for 20 amino acids. In this research, scientists replaced the UAG codon with the UAA codon. As a result, viruses introduced into genomically recoded E. coli that contain the eliminated UAG codon cannot properly produce and express the protein necessary to infect the organism, Isaacs said, and the organism is resistant to that virus.
The researchers’ success can help solve two of the biotechnology industry’s unsolved problems: bio-safety and virus infection, particularly in processes that rely on organisms. Large bodies of organisms, which are used to produce compounds, drugs and other chemicals, are often compromised by a virus or phage infection and turned into “two million liters of useless fluid,” Harvard Medical School professor of genetics and senior co-author George Church said. However, through the use of genomically recoded organisms, industries might be able to counter those deleterious effects and make the processes more stable, Church said.
Isaacs and Church also showed that eliminating the UAG codon frees up a protein coding space in an organism’s genome, allowing for a more efficient incorporation of non-standard amino acids — amino acids that are not traditionally coded for. Normally, non-standard amino acids must compete with naturally-occurring amino acids to be synthesized into a protein, Church said.
Yet after the deletion of the UAG codon, the codon can be reintroduced back into the genome with a new non-standard amino acid associated with it.
“We now have a dedicated codon that will allow us to very efficiently introduce the 21st amino acid with new chemical properties, which will allow us to change the function and stability of the protein and create new types of drugs,” Isaacs said. “We’re really opening up a new spectrum of chemical proteins.”
Having proven the ability to establish viral resistance via genomic recoding in E.coli, researchers are interested in applying this technology to other organisms in the the dairy industry and pharmaceuticals for which viruses are a problem.
The technology in genomic recoding of E. coli is applicable to other organisms in principle, Church said.
Professor of biological engineering at the Massachusetts Institute of Technology Timothy Lu said the studywas a major advance over other genomic studies, adding that the technique which the reseachers developed should be translatable across organisms.
“They’re just scratching what’s possible,” said Lu. “Now the question is, can they re-encode larger subsets of functions inside the cell and do larger things. It seems promising in this technology.”
Apart from Harvard and Yale, study collaborators included MIT, the Scripps Research Institute and Columbia.