The first cells reprogrammed to make synthetic polymers-and virus-resistant pharmaceutical companies

Scientists have followed gene-encoded instructions to develop the first cells that can build artificial polymers from building blocks not found in nature.

In this study, led by scientists at the MRC Laboratory of Molecular Biology in Cambridge, England, Synthetic genome made Bacteria It is completely resistant to viral infections.

Scientists say their research could lead to the development of new polymers, large molecules made up of many repeating units, such as many drugs, including proteins, plastics, and antibiotics.

Studies published today in the journal Science, If built on the basis of previous breakthrough work by the team In 2019, They have developed a new technology to create the largest synthetic genome ever. In other words, the entire genome of E. coli is constructed from scratch.

Utilize the cell’s natural protein production process

The goal of scientists was to use their new technology to create the first cell in which a polymer could be completely assembled from components not found in nature.

Protein is a kind polymerScientists sought to take advantage of cells’ natural protein-producing processes to create artificial polymers.

The genetic code tells cells how to make proteins. Proteins are built by stitching together strings of natural components. amino acid..

The genetic code of DNA consists of four bases, represented by the letters A, T, C, and G. The four letters in DNA are “read” in groups of three letters (for example, “TCG”). “Codon”

Each codon tells the cell to add a specific amino acid to the chain, which is done via a molecule called a “tRNA”. “TCG” brings the amino acid serine.

If there are 4 characters in 3 groups, there are 64 character combinations. However, there are only 20 natural amino acids that cells normally use. Therefore, several different codons are synonymous and all encode the same amino acid. For example, TCG, TCA, AGC, and AGT all code for serine.

There are also codons, such as TAG and TAA, that tell cells when to stop producing proteins.

Whole genome rewriting

When the team at the MRC Laboratory of Molecular Biology created the first whole genome synthesized from scratch for the commonly studied bacterium E. coli in 2019, they have the opportunity to simplify that genome. I also used it.

They replaced some codons with their synonyms. Removed all instances of TCG and TCA and replaced them with synonyms AGC and AGT.

They also removed all instances of the “stop” codon TAG and replaced it with the synonym TAA.

The modified bacterium did not have TCG, TCA, or TAG codons in its genome, but was able to make normal proteins and grow alive.

Strong against viruses

In this latest study, scientists have further modified the bacteria to remove tRNA molecules that recognize codons TCG and TCA. This means that even if the genetic code has TCG or TCA codons, the cell no longer has molecules to read those codons.

This is fatal to viruses that try to infect cells. This is because the virus replicates by injecting the genome into the cell and hijacking the cell’s machine. The viral genome still contains many TCG, TCA, and TAG codons, but the modified bacterium does not have the tRNA to read these codons.

When a modified bacterial machine attempts to read the viral genome, it fails each time it reaches the TCG, TCA, or TAG codon.

In this study, researchers infected the bacteria with a cocktail of viruses. Normal unmodified bacteria were killed by the virus, but modified bacteria were resistant to infection and survived.

Making bacteria resistant to viruses makes it possible to make certain types of drugs more reliably and cheaply. For example, protein drugs such as insulin and many drugs, such as polysaccharides and protein subunit vaccines, are made by growing bacteria that contain instructions for making the drug.

Professor Jason Chin of the MRC Laboratory of Molecular Biology, who led the study, said: Virus Invasion of a tank of bacteria used to make certain drugs can destroy the entire batch. Our modified bacterial cells were completely resistant to the virus and were able to overcome this problem. The virus uses the complete genetic code, so the modified bacterium cannot read the viral gene. “

Living factory of synthetic polymers

By creating bacteria in a synthetic genome that does not use specific codons, researchers have freed those codons for other purposes, such as coding synthetic building blocks called monomers.

“This system allows us to write genes that encode instructions for making polymers from non-naturally occurring monomers,” said Professor Chin.

“These bacteria have the potential to be transformed into regenerative and programmable factories, producing a wide range of new molecules with new properties, including the production of new drugs such as new antibiotics and biotechnology. It has the potential to benefit medicine. “

“We would like to use these bacteria to discover and build long synthetic polymers that have the potential to form structures and form new types of materials and medicines. We are also investigating the application of this technology. , Develop new polymers such as biodegradable plastics, which may contribute to the circulating bioeconomy. “

They manipulated the bacteria to produce tRNAs bound to artificial monomers that recognize newly available codons (TCG and TAG).

They inserted a gene sequence containing a string of TCG and TAG codons into bacterial DNA. These were read by modified tRNAs that assemble the strands of synthetic monomers in a sequence defined by the sequence of DNA codons.

The cells were programmed to connect the monomers in different orders by altering the order of the TCG and TAG codons in the gene sequence.

By changing the monomer that binds to the tRNA, a polymer composed of different monomers was also created.

Researchers were able to create a polymer that stitched together up to eight monomers. They joined the ends of these polymers to form a macrocyclic molecule. Macrocyclic molecules are a type of molecule that forms the basis of drugs such as certain antibiotics and anticancer drugs.

In this study, the synthetic monomers were bound by the same chemical bond that binds the amino acids of the protein, Researchers are investigating How to extend the range of bonds that can be used with new polymers.

Dr. Megan Dawley, Head of Molecular Cell Medicine at the Medical Research Council, who funded the study, said: Genetic code The expansion is a very exciting example of the value of MRC’s long-term commitment to discovery science. Such research in synthetic and engineering biology has great potential to have a significant impact on biopharmacy and other industrial environments. ”

Provided by UK Research and Innovation