From First Principles Optovolution: Teaching Proteins to Think Like Computers (EP. 31)
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Mar 18, 2026 A deep dive into a synthetic‑biology breakthrough that uses light and the cell cycle to evolve proteins that toggle rather than stay always on. They explain coupling oscillators to select for dynamic behavior, engineering color‑multiplexed light sensitivity, and creating a single‑protein logic gate that performs time‑sensitive AND operations. Future directions for programmable cellular software are discussed.
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Directed Evolution Favors Always On Proteins
- Directed evolution normally selects for proteins that are continuously active rather than dynamic toggling molecules.
- Krishna Choudhary explains classic protocols keep selection pressure constant (toxin baths), so surviving variants are 'always on' enzymes rather than state-switching proteins.
Use Cell Cycle Oscillators To Evolve Dynamic Proteins
- Coupling an external light oscillator to the cell cycle forces selection for proteins that must toggle in sync with cellular rhythms.
- Krishna ties the protein's survival to CLB5 cyclin pulses so mutants stuck on or off cause cell death and are removed by evolution.
Force Dependence By Deleting Endogenous Cyclins
- Make a yeast strain dependent on externally controlled cyclin expression so only light-responsive, time-varying transcription factors survive.
- Krishna describes Dajbog yeast with endogenous cyclins deleted and CLB5 placed under the evolved protein's control.