Subhajit Nan, Amity University, Kolkata
Scientists created modified virus-resistant bacteria and made synthetic polymers from synthetic building blocks, making them immune to viral attack. They also found the synthetic genome made the bacteria fully proof against infection by viruses.
Using the natural protein-making processes of the cell
The goal was to utilize the newly available technology to create a genetically modified bacterial cell that will be able to assemble polymers from building blocks (monomers) that aren’t found naturally. They wanted to make artificial polymers by using the natural protein-making processes of the cell to their advantage.
The genetic code of the DNA decides the protein synthesis of a cell. They are constructed by joining together amino acids. The DNA comprises four nitrogenous bases, namely, Adenine, Thymine, Cytosine, and Guanine, which are represented by the letters A, T, C, and G respectively. They’re ‘read’ in groups of three letters, for example, ‘TCG’, which are called a ‘codon’.
Each codon is responsible for the addition of a specific amino acid to the chain. It does this through molecules called ‘tRNA’. Each codon has a specific tRNA molecule that recognizes it and codes for the corresponding amino acid. For example, the tRNA that recognizes TCG, codes for serine amino acid.
Only 20 different natural amino acids, out of the 64 possible combinations of letters, are commonly used by cells. Hence, several different codons can be synonymous, i.e., they all code for the same amino acid. For example, TCG, TCA, AGC, and AGT all code for serine amino acids. Some codons instruct a cell to stop protein syntheses, such as TAG and TAA. They are called “stop-codons”.
Re-writing the whole genome
Earlier, when this same team of scientists created the first entire genome synthesized from scratch for the E. coli bacteria, they also simplified its genome.
They replaced some of the codons with their synonyms, i.e., they removed every instance of TCG and TCA and replaced them with the synonyms AGC and AGT. They removed the TAG stop-codon at every instance and replaced it with its synonym TAA.
The genetically modified bacteria, now, no longer had the codons TCG, TCA, and TAG in their genome, however, they could still make normal proteins and perform all metabolic activities normally.
Creation of the modified virus-resistant bacteria
Now, they have further genetically modified the bacteria to remove the tRNA molecules that recognize the codons TCG and TCA. This implies that even if there are TCG or TCA codons in the genetic code, the cell no longer can read them.
This is fatal for any virus that tries to infect the cell because viruses (like bacteriophages) replicate by injecting their genome into a cell and taking over the cell’s total machinery. Virus genomes contain the TCG, TCA, and TAG codons, but the modified bacteria are missing the tRNA molecules to read these codons. So, when the cell of the genetically modified bacteria attempts to translate the viral genome, it fails every time it reaches a TCG, TCA, or TAG codon, and hence, replication of the virus fails to happen.
In this research, they infected their bacteria with a set of viruses. Normal un-engineered bacteria were killed by the viruses, but the genetically modified bacteria, being resistant to the viral infection, survived.
Biological factories for synthetic polymers
By creating genetically modified bacteria with synthetic genomes that do not use certain codons, the scientists had freed up those codons to be available to be used for other purposes, such as preparation of synthetic monomers, which are not available naturally.
Tasks are undertaken here by the scientists
- They engineered the bacteria to produce tRNAs coupled with artificial monomers, which recognized the newly available codons (TCG and TAG).
- They inserted genetic sequences with strings of TCG and TAG codons into the bacteria’s DNA. These were read by the modified tRNAs, which assembled chains of synthetic monomers in that sequence defined by the sequence of codons in the DNA.
- The cells were programmed to stitch together monomers in different orders by changing the order of TCG and TAG codons in the genetic sequence.
- Polymers composed of different monomers were also made by changing the monomers that were coupled to the tRNAs.
- The researchers were able to create polymers made of up to eight monomers stitched together. They joined the ends of these polymers together to make macrocycles, which is a type of molecule that forms the basis of some drugs.
- The synthetic monomers were linked together by the same chemical bonds that join together amino acids in proteins.
We can say that Dr. Chin’s pioneering work into genetic code expansion has huge potential for a major impact in biopharma and other industrial fields.
Uses of these genetically modified Virus-Resistant Bacteria
These genetically modified bacteria may be turned into biological factories that produce a wide range of new molecules with novel properties, which could benefit biotechnology and medicine, such as making new drugs (like new antibiotics). Making bacteria resistant to viral attack could make manufacturing certain types of drugs commercially more reliable and cheaper.
These bacteria can be used to discover and build long synthetic polymers that might have the ability to form new materials and medicines. This technology can be used to develop novel polymers, such as biodegradable plastics, which can contribute to a circular bio-economy.
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Reference:
- Robertson, W. E., Funke, L., de la Torre, D., Fredens, J., Elliott, T. S., Spinck, M., Christova, Y., Cervettini, D., Böge, F. L., Liu, K. C., Buse, S., Maslen, S., Salmond, G., & Chin, J. W. (2021). Sense codon reassignment enables viral resistance and encoded polymer synthesis. Science (New York, N.Y.), 372(6546), 1057–1062. https://doi.org/10.1126/science.abg3029
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