Refactored Genetic Codes for HGT-Resistant Cells
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Solution Overview
Problem
The near-universal genetic code allows for horizontal gene transfer (HGT) between organisms, facilitating evolutionary innovation but also enables mobile genetic elements like transposons and viruses to exploit host cells, posing a liability by propagating at the expense of the host.
Innovation Solution
Refactoring the genetic code of a synthetic E. coli strain to exhibit semantic- and functional orthogonality with the universal genetic code by recoding sense codons to distinct canonical amino acids, creating cells resistant to horizontal gene transfer and mobile genetic elements.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If the near-universal genetic code is maintained to allow horizontal gene transfer and evolutionary innovation, then genetic information can be shared between organisms, but mobile genetic elements can exploit the common code to propagate at the expense of host cells
Solution Approach 1:
The patent applies parameter changes by systematically recoding multiple sense codons (TCG, TCA, TGG) to assign them to different amino acids than in the universal genetic code. This fundamental parameter change in codon-amino acid mapping creates genetic orthogonality that prevents mobile genetic elements from being read by host machinery, thereby blocking their exploitation while maintaining the host's ability to express its own refactored genome
Solution Approach 2:
The invention segments the genetic code by dividing it into orthogonal subsets - the host uses a refactored code while mobile genetic elements use the universal code. This segmentation creates functional separation where the host's translational machinery can only read genes with the refactored code, effectively isolating the host from harmful mobile elements that rely on the universal code
2Reliability
If sense codons are reassigned to distinct canonical amino acids to create genetic orthogonality, then resistance to mobile genetic elements is achieved, but the complexity of genome synthesis and validation increases
Solution Approach 1:
The patent applies preliminary action by performing comprehensive genome synthesis and recoding before introducing the organism to environments with mobile genetic elements. The entire genome is systematically rewritten with refactored codons in advance, and the organism is validated for proper expression and function before deployment, preventing subsequent contamination issues
Solution Approach 2:
The invention systematically changes multiple genetic code parameters simultaneously - recoding TCG to alanine, TCA to histidine, and TGG to tryptophan - creating a coordinated set of parameter changes that collectively achieve genetic orthogonality. This multi-parameter approach ensures comprehensive protection while maintaining internal consistency of the refactored genome
Data Source
AI summary
Provided are cells that are resistant to mobile genetic elements or horizontal gene transfer, and methods for obtaining said cells. Also provided are methods for preventing the horizontal transfer of genetic information between a mobile genetic element and a first cell, cells making use of new genetic codons schemes and related subject matter, kits comprising mutually orthogonal cells, and mobile genetic elements. Also provided are methods of altering the susceptibility of a gene to mutations that alter the encoded amino acid sequence, methods for evolving or improving a protein, and methods for rendering a target gene more resistant to mutation. Additionally provided are uses of the cells for making polymers and methods comprising using the cells for making polymers.