A bacterial virus inserting genetic material inside a bacterial cell during infection.
A bacterial virus inserting genetic material inside a bacterial cell during infection.
Image courtesy of Behnoush Hajian.

The Science

Genome engineering allows scientists to modify the genetic code of microbes. Now, researchers have engineered the genome of the bacterium Escherichia coli (E. coli) to make it immune to viral infections. These infections often cause bacterial cultures to fail. The researchers also equipped the engineered strain with safety features that block the unwanted transfer of genetic material to other bacteria. These features work as a biosecurity device to prevent the engineered bacteria from surviving outside the lab. To further enhance its biosafety, the researchers designed the strain to depend on an amino acid that is not found in nature. This amino acid must be supplied to the culture to allow the bacteria to grow. 

The Impact

Biomanufacturing uses bacteria like E. coli as “bio-factories” to produce chemicals, biomaterials, and biofuels. This involves growing large bacterial cultures. These cultures face the risk of viral infections. This can lead to the collapse of the bacterial culture, halting production. Another risk is that engineered organisms can escape to the environment. There, they can transfer their engineered genes to other organisms. This work provides a new genome engineering technology that significantly reduces the likelihood of this viral contamination. It has built-in biosafety measures to prevent the engineered microbe from growing outside the laboratory and transferring its genetic material. The technology will expand the range of applications and the commercial potential of engineered microbes.

Summary

Most living organisms use the same genetic code written in their DNA. The DNA code consists of four letters that can form 64 three-letter words (or codons). The cell “expresses” the observable traits encoded in its genes by translating each codon into one of the 20 building blocks (called amino acids) that form proteins. To build its proteins, the cell adds each amino acid using a specific transfer ribonucleic acid (tRNA), which “reads” the corresponding codon. In some cases, several different codons correspond to the same amino acid because the genetic code has 64 codons for 20 amino acids. 

To find out if genome engineering can confer virus resistance to bacteria, researchers tested a “recoded” E. coli strain whose genetic code had been reprogrammed to use only 61 codons instead of 64. They expected that viruses would be unable to infect the recoded strain because viral genes use all 64 codons. However, some viruses contained their own tRNAs and were therefore able to infect the recoded strain. To circumvent this, the researchers further engineered the strain with additional tRNAs that add a different amino acid than the one encoded by certain codons. When viruses try to infect these engineered cells, the viral proteins are improperly translated, killing the virus. This same effect prevents the recoded strain genes from being expressed if they jump into other bacteria. Finally, the new recoded strain also requires a synthetic amino acid to survive, ensuring it cannot grow outside the laboratory. This “genetic firewall” between the engineered bacteria and other microorganisms enables the study of new biological functions and makes genetically modified bacteria much safer to use for applications such as biomanufacturing.

Contact

George Church
Harvard Medical School, Wyss Institute
gchurch@genetics.med.harvard.edu
church_lab_admin@hms.harvard.edu

Akos Nyerges
Harvard Medical School, Department of Genetics
akos_nyerges@hms.harvard.edu

Funding

This research was supported by the Department of Energy Office of Science, Office of Biological and Environmental Research, and by the National Science Foundation, the National Institutes of Health, and by the European Molecular Biology Organization.

Publications

Nyerges, A., et al., A swapped genetic code prevents viral infections and gene transfer. Nature 615, 720–727 (2023). [DOI: 10.1038/s41586-023-05824-z]

Related Links

New Synthetic E.coli Is Immune to Bacteriophage Infection, The Scientist

George Church’s Lab Engineers Virus Resistant Bacterium With Synthetic Genome, Genetic Engineering and Biotechnology News