PopQC Biosensor System for Cell Population Enrichment

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Solution Overview

Problem

Biosynthetic performance in bioproduction is suboptimal due to cell-to-cell variations in isoclonal populations, leading to subpopulations of low- and high-performing variants, where low-performing variants consume nutrients without efficiently synthesizing products, resulting in suboptimal ensemble performance.

Innovation Solution

The implementation of an in vivo population quality control (PopQC) system using a host cell with a product-responsive biosensor and a selection gene, which continuously enriches high-performing, non-genetic variants by regulating the expression of a selection gene based on product levels, thereby enhancing biosynthetic performance.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If isoclonal populations are used for biosynthesis, then genetic uniformity is maintained, but cell-to-cell variations cause suboptimal ensemble performance due to low-performing variants consuming nutrients inefficiently

Engineering Contradiction:

Improvebiosynthetic product yieldVSAvoidbiosynthetic performance consistency

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent implements a feedback mechanism where a biosensor detects product concentration and regulates selection gene expression accordingly. High-performing cells that produce sufficient product activate the selection gene, while low-performing cells do not, creating a feedback loop that continuously enriches the population for high producers and resolves the contradiction between productivity and performance consistency

Inventive Principle:

Principle #23Feedback

Solution Approach 2:

The patent changes the expression level parameter of the selection gene based on product concentration. By dynamically adjusting gene expression thresholds, the system adapts to population performance variations, allowing only cells meeting a certain productivity threshold to express the selection gene, thereby improving both overall productivity and performance reliability

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If non-genetic cell-to-cell variation is present, then population diversity increases, but low-performing variants reduce overall biosynthetic efficiency

Engineering Contradiction:

Improvepopulation heterogeneityVSAvoidensemble biosynthetic performance

Core Design Contradiction:

Adaptability or versatilityVSProductivity

Solution Approach 1:

The feedback-regulated selection system monitors product levels and selectively amplifies high-performing variants while suppressing low-performers, converting population heterogeneity from a detrimental factor into a beneficial resource for continuous performance improvement

Inventive Principle:

Principle #23Feedback

Solution Approach 2:

The patent converts the harmful effect of population heterogeneity into a benefit by using the existing non-genetic variation as a substrate for selection. The biosensor-selection gene system acts as a filter that transforms diverse population into an enriched high-performing population, turning the problem of variation into a solution for performance enhancement

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS11661615B2Biosynthesis method with host cell and quality control system

Publication Date: 2023.05.30 WASHINGTON UNIV IN SAINT LOUIS

AI summary

Systems, methods, and host cells utilizing a PopQC construct for enhancing product biosynthesis by exploitation of non-genetic cell-to-cell variation are disclosed. The PopQC construct includes at least a product-responsive biosensor and a selection gene.