Cells with synthetic genomes reprogrammed at MRC LMB in Cambridge - and could create new drugs or biodegradable plastics
A potentially revolutionary step forward in biology – which could lead to more reliable drug manufacture, new antibiotics or biodegradable plastics – has been achieved at the MRC Laboratory of Molecular Biology in Cambridge.
Two years on from creating the biggest ever synthetic genome, the laboratory of Professor Jason Chin has now reprogrammed cells to make artificial polymers from building blocks not found in nature.
They were able to direct the cells by encoding instructions in their genes – and they proved that their synthetic genome also made them entirely resistant to infection by viruses.
The research could lead to the creation of entirely new polymers – large molecules made of many repeating units, as seen in proteins, plastics and many drugs.
Prof Chin said: “This system allows us to write a gene that encodes the instructions to make polymers out of monomers that don’t occur in nature.
“These bacteria may be turned into renewable and programmable factories that produce a wide range of new molecules with novel properties, which could have benefits for biotechnology and medicine, including making new drugs, such as new antibiotics.
“We’d like to use these bacteria to discover and build long synthetic polymers that fold up into structures and may form new classes of materials and medicines.
“We will also investigate applications of this technology to develop novel polymers, such as biodegradable plastics, which could contribute to a circular bioeconomy.”
It follows pioneering work, completed in 2019, which enabled the group to construct the entire genome of the bacterium Escherichia coli (E. coli) from scratch.
As the Cambridge Independent reported at the time, they had created a new lifeform that played by different biological rules to any other before it.
And they did so by answering a long-standing question about the way genetic code is read.
DNA is made up of four bases, which are represented by the letters A, T, C and G.
These are ‘read’ by machinery in cells in threes, such as TCG, and each of these groups is called codon.
To build proteins, each codon tells the cell to add a specific amino acid to a chain via molecules called ‘tRNA’. And each codon has a specific tRNA that recognises it and adds the corresponding amino acid. The tRNA that recognises the codon ‘TCG’, for example, leads to the amino acid serine.
In all known life, there are 64 codons, or possible combinations, yet only 20 natural amino acids. This means there is redundancy in the system. For example, TCG, TCA, AGC and AGT all code for serine.
Other codons – such as TAG and TAA – send stop signals to tell a cell when to stop making a protein.
When they synthesised the entire genome of the commonly studied bacteria, E. coli, in 2019, Prof Chin’s group also simplified its genome, giving it just 61 codons.
Like a giant find and replace exercise, they removed every instance of TCG and TCA and replaced them with the synonyms AGC and AGT, while every instance of the stop codon TAG was replaced by another, TAA.
Their creation continued to synthesise all the normal proteins and the cells containing the synthetic genome thrived.
For the new work, they aimed to use their new techniques to make artificial polymers by exploiting cells’ natural protein-making processes.
They further modified the bacteria to remove the tRNA molecules that recognise the codons TCG and TCA.
It means that even if there are TCG or TCA codons in the genetic code, the cell no longer has the molecule that can read those codons.
And that is fatal for any virus that tries to infect the cell, as viruses replicate by injecting their genome into a cell and hijacking the cell’s machinery.
But when the machinery in the modified bacteria tries to read the virus genome, it fails every time it reaches a TCG, TCA or TAG codon.
The researchers infected their bacteria with viruses to test what happened. While the unmodified normal bacteria were killed, the modified bacteria were resistant to infection and survived.
This could be very useful in improving the reliability and cost of drug manufacture.
Medicines such as protein drugs, like insulin, and polysaccharide and protein subunit vaccines, are manufactured by growing bacteria that contain instructions to produce the drug.
“If a virus gets into the vats of bacteria used to manufacture certain drugs then it can destroy the whole batch,” said Prof Chin. “Our modified bacterial cells could overcome this problem by being completely resistant to viruses. Because viruses use the full genetic code, the modified bacteria won’t be able to read the viral genes.”
Freeing up certain codons also means they are available for use for other purposes, such as coding for synthetic building blocks, called monomers.
The team engineered the bacteria to produce tRNAs coupled with artificial monomers that recognised the newly-available codons TCG and TAG.
Genetic sequences with strings of TCG and TAG codons were inserted into the bacteria’s DNA and read by the altered tRNAs.
This assembled chains of synthetic monomers in the order defined by the sequence of codons in the DNA.
They were able to programme the cells to string together monomers in different orders by changing the order of TCG and TAG codons in the genetic sequence. And they were able to create polymers composed of different monomers by changing which monomers were coupled to the tRNAs.
Polymers comprising up to eight monomers strung together were created.
The ends of these were joined to make macrocycles, which is a type of molecule that forms the basis of some drugs, including certain antibiotics and cancer drugs.
The synthetic monomers were linked using the same chemical bonds that join amino acids in protein, but the team is also exploring how to expand the range of linkages that could be used in the new polymers.
Dr Megan Dowie, head of molecular and cellular medicine at the Medical Research Council, which funded the study, said: “Dr Chin’s pioneering work into genetic code expansion is a really exciting example of the value of our long-term commitment to discovery science. Research like this, in synthetic and engineering biology, clearly has huge potential for major impact in biopharma and other industrial settings.”
The study, published in Science, was funded by the MRC and the European Research Council.