The fast expansion of RNA-based medicine requires the quick production of high-quality RNA, which has unfortunately remained a technical hurdle. Natural enzymes excel at copying DNA but struggle to synthesize RNA at the speeds needed for clinical research. 

University of California, Irvine researchers, led by Prof. John Chaput, addressed this challenge by developing C28, a synthetic polymerase. Unlike standard laboratory enzymes, C28 synthesizes RNA with an efficiency and accuracy that mirror natural DNA replication. 

Rather than attempting to manually re-engineer the complex architecture of a polymerase, the UC Irvine team utilized a high-throughput directed evolution strategy. By screening millions of enzyme variants simultaneously through a single-cell platform, the researchers allowed natural selection to identify the most effective mutations.

The resulting C28 enzyme surprised the team by functioning through a distributed network of mutations rather than changes to a single, localized area.

Chaput said:

“DNA polymerases are naturally designed to reject RNA. What surprised us is that we were able to overcome this barrier not by redesigning the enzyme’s active site, but by letting evolution find unexpected structural solutions.”

The utility of C28 extends beyond simple RNA synthesis. The enzyme demonstrates a unique poly-functional capability: it can perform reverse transcription (converting RNA back into DNA) and generate hybrid DNA-RNA molecules within standard PCR workflows.

Crucially for the biotech sector, C28 is compatible with the chemically modified building blocks required for stable therapeutic RNA. This versatility makes it an ideal candidate for manufacturing complex, customized sequences that are often difficult for existing enzymes to process.

The study, published in Nature Chemical Biology, suggests that the limits of enzyme functionality are much wider than previously assumed. By prioritizing evolutionary screening over manual design, the researchers have unlocked a level of molecular performance that does not exist in nature.

He added:

“This work shows that enzymes are far more adaptable than we once thought. By harnessing evolution, we can create new molecular tools that open the door to advances in RNA biology, synthetic biology and biomedical innovation.”

Read the full article here to learn more about the synthetic enzyme.

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