Recoded Bacterial Organisms for Phage-Resistant Biologics Manufacturing
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Solution Overview
Problem
There is a need for methods to produce nucleic acids and amino acid polymers that are more time-effective, cost-effective, and scalable, while adhering to current good manufacturing practices (cGMP) or non-cGMP conditions, particularly for therapeutic biologics such as vaccines and cell therapies.
Innovation Solution
The development of genetically engineered bacterial organisms with engineered genetic material, including recoded codons and exogenous nucleic acid sequences, which enable continuous cGMP manufacturing of therapeutic polypeptides with enhanced viral resistance and productivity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional bacterial systems are used for manufacturing therapeutic polypeptides, then production can proceed with standard genetic material, but manufacturing duration is limited and productivity decreases in the presence of phages
Solution Approach 1:
The patent applies parameter changes by recoding specific codons (e.g., changing TAA stop codons to TAG) in the bacterial genome and corresponding tRNA sequences. This fundamental parameter change in the genetic code creates a mismatch that prevents phage recognition and infection, thereby improving viral resistance while maintaining manufacturing productivity
Solution Approach 2:
The patent converts the harmful effect of phage infection into a benefit by using phage-resistant bacterial strains with recoded genomes. The recoding that originally aimed to prevent phage infection is now leveraged to sustain continuous manufacturing operations, turning a defensive mechanism into a productivity-enhancing feature
2Duration of action of stationary object
If manufacturing continues in the presence of phages, then operational continuity is maintained, but manufacturing duration is reduced and efficiency decreases
Solution Approach 1:
The patent applies preliminary action by pre-recoding the bacterial genome and tRNA sequences before manufacturing begins. This preparatory genetic modification establishes phage resistance in advance, allowing continuous manufacturing operations to proceed without interruption or efficiency loss during phage exposure
Solution Approach 2:
The patent enables continuity of useful action by creating bacterial strains that can maintain therapeutic polypeptide production continuously despite phage presence. The recoded genetic system ensures uninterrupted manufacturing, sustaining both duration and efficiency throughout the production process
3Reliability
If standard codon usage is maintained, then genetic material functions normally, but recoded codons and tRNA modifications are needed to achieve viral resistance
Solution Approach 1:
The patent applies local quality by making targeted, localized changes to specific codons and their corresponding tRNA sequences rather than comprehensively recoding the entire genome. This selective approach achieves viral resistance through precise local modifications, minimizing overall genetic complexity while maintaining functionality
Data Source
AI summary
Provided herein are methods of generating engineered organisms with targeted genome designs, such as recoding designs, and targeted functional properties. Also provided are methods of generating biomanufacturing engineered organisms and uses thereof for production of biomanufactured products.