Scripps Research scientists unveiled T7-ORACLE, a platform that accelerates protein evolution by 100,000 times the natural rate. It runs inside living E. coli and confines mutations to plasmids, preserving the host genome and enabling continuous selection cycles.
The system synchronizes mutation with bacterial division, turning each 20-minute doubling into a fresh evolutionary round. Researchers reported rapid gains in enzyme performance in days, compressing iterative lab workflows into a streamlined, in-cell engine.
The orthogonal replication breakthrough
T7-ORACLE installs a T7 bacteriophage-derived DNA replication system alongside the bacterial machinery. This orthogonal replisome replicates only a target plasmid, leaving the chromosome untouched and protecting cell fitness during high-rate mutation.
Engineers tune the T7 polymerase to be error-prone on the plasmid cargo. The host genome remains stable, so cells tolerate sustained hypermutation while continuing to grow, divide, and feed selection pressure.
Did you know?
Early continuous evolution systems like PACE used bacteriophages to evolve proteins in hours. T7-ORACLE brings that speed inside cells while keeping the host genome intact.
How continuous in-cell evolution works
A gene of interest is cloned onto the T7-replicated plasmid. As cells divide, the error-prone T7 polymerase diversifies that gene at extreme rates. Selection conditions enrich improved variants without manual cloning cycles.
Because each cell cycle provides mutation and selection, the process becomes hands-off and quick. Researchers can track fitness gains over successive doublings and adjust pressures to guide functional outcomes.
Demonstrated speed and real-world relevance
Using an antibiotic resistance enzyme as a test bed, the team evolved variants that tolerated drug concentrations thousands of times higher than the ancestor in under a week. Key mutations echoed patterns seen in clinical resistance.
Mirroring real-world trajectories validates the system’s fidelity to functional landscapes. It suggests T7-ORACLE can surface clinically meaningful solutions while exploring broader variant space at speed.
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Why sparing the genome matters
High mutation rates often damage host chromosomes, collapsing growth and experiments. By restricting errors to plasmids, T7-ORACLE keeps cells healthy, supports long runs, and avoids genome instability that confounds results.
Genome sparing also reduces off-target artifacts. Researchers can attribute functional changes to plasmid-borne genes and refine selection schemes with clearer causal signals.
From weeks to days: a workflow shift
Traditional directed evolution requires iterative cloning, transformation, and screening. T7-ORACLE folds those steps into continuous culture, where evolution proceeds with minimal handling and frequent measurable gains.
This shift lowers labor and accelerates learning. Teams can run more targets, explore tougher landscapes, and iterate on conditions to shape trajectories in near real time.
Applications across medicine and industry
Therapeutic enzymes and proteases can be tuned for stability, specificity, and activity. Antibody fragments and binders may gain affinity or resilience. Industrial biocatalysts can be optimized for solvents, temperature, and throughput.
Rapid resistance modeling can also inform drug design. By evolving escape variants quickly, researchers can anticipate vulnerabilities and develop more robust therapeutic strategies.
Accessibility without specialized hardware
The platform integrates with standard E. coli workflows, culture equipment, and selection assays. Labs can adopt it without building custom devices, expanding access to high-velocity evolution.
Modular plasmid design allows drop-in genes from human, viral, or microbial sources. The same chassis supports many targets, reducing setup time between projects.
Guardrails, risks, and responsible use
Hypermutation demands careful containment and biosafety practices. Selection pressures should be calibrated to avoid runaway traits and to maintain understandable fitness gradients.
For resistance studies, strict controls and disposal protocols limit environmental risk. Ethical guidelines and institutional oversight remain central to deployment.
What to watch next
Anticipate receiving reports on clinically relevant enzymes, next-generation binders, and multi-trait optimization that balances both activity and stability. Combinatorial selections may evolve function plus manufacturability.
As datasets grow, model-guided evolution could pair with T7-ORACLE to navigate landscapes more efficiently. The frontier blends statistical insight with cellular speed to unlock harder protein design goals.
Bottom line
T7-ORACLE delivers a genome-sparing, orthogonal replication engine that hypermutates plasmid genes in sync with cell division. It turns bacterial growth into a rapid evolution loop, opening faster paths to proteins that matter in clinics and industry.
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