At Scripps Research, scientists have created T7-ORACLE, a synthetic biology platform designed to supercharge protein evolution inside living cells. The system reprograms E. coli bacteria to host a second DNA replication process, borrowed from bacteriophage T7, that operates independently of the cell’s own genome replication. This orthogonal replication targets only plasmid DNA, allowing researchers to introduce mutations at rates up to 100,000 times higher than natural mutation levels without harming the host cell.
In traditional directed evolution, scientists cycle through rounds of DNA modification, expression, and selection, often taking a week or more per round. T7-ORACLE bypasses these delays by coupling mutation and selection to the bacterial division cycle, generating a new evolutionary round every 20 minutes. This allows continuous, high-speed adaptation without labor-intensive intervention or complex equipment.
To showcase the technology, researchers inserted a well-known antibiotic resistance gene, TEM-1 β-lactamase, into the system and subjected the bacteria to increasing doses of multiple antibiotics. Within a week, the evolved enzymes could withstand antibiotic concentrations 5,000 times higher than the starting strain. Many resulting mutations matched those seen in clinical drug-resistant bacteria, with some combinations proving even more potent.
The platform’s strength lies in its flexibility. Any gene, whether from humans, viruses, or other organisms, can be loaded into plasmids for rapid optimization. Potential applications range from developing targeted antibodies and therapeutic enzymes to evolving proteases that attack cancer-related proteins.
Because T7-ORACLE integrates seamlessly with standard E. coli workflows, it lowers barriers for adoption across academic and industrial labs. Researchers see it as a tool not only for accelerating drug discovery but also for exploring synthetic genomics, including evolving enzymes that work on entirely artificial genetic materials.
Source: 10.1126/science.adp9583
At Scripps Research, scientists have created T7-ORACLE, a synthetic biology platform designed to supercharge protein evolution inside living cells. The system reprograms E. coli bacteria to host a second DNA replication process, borrowed from bacteriophage T7, that operates independently of the cell’s own genome replication. This orthogonal replication targets only plasmid DNA, allowing researchers to introduce mutations at rates up to 100,000 times higher than natural mutation levels without harming the host cell.
In traditional directed evolution, scientists cycle through rounds of DNA modification, expression, and selection, often taking a week or more per round. T7-ORACLE bypasses these delays by coupling mutation and selection to the bacterial division cycle, generating a new evolutionary round every 20 minutes. This allows continuous, high-speed adaptation without labor-intensive intervention or complex equipment.
To showcase the technology, researchers inserted a well-known antibiotic resistance gene, TEM-1 β-lactamase, into the system and subjected the bacteria to increasing doses of multiple antibiotics. Within a week, the evolved enzymes could withstand antibiotic concentrations 5,000 times higher than the starting strain. Many resulting mutations matched those seen in clinical drug-resistant bacteria, with some combinations proving even more potent.
The platform’s strength lies in its flexibility. Any gene, whether from humans, viruses, or other organisms, can be loaded into plasmids for rapid optimization. Potential applications range from developing targeted antibodies and therapeutic enzymes to evolving proteases that attack cancer-related proteins.
Because T7-ORACLE integrates seamlessly with standard E. coli workflows, it lowers barriers for adoption across academic and industrial labs. Researchers see it as a tool not only for accelerating drug discovery but also for exploring synthetic genomics, including evolving enzymes that work on entirely artificial genetic materials.
Source: 10.1126/science.adp9583
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