Editorial: Synthetic biology and therapeutic applications of transfer RNA
Bibliographic record
Abstract
Because of their central role in protein synthesis, engineered and synthetic tRNAs emerged as essential components of orthogonal translation systems that are designed to incorporate noncanonical or even unnatural amino acids into proteins in cells and cell-free systems. Furthermore, recent efforts have used either normal wild-type or engineered tRNAs to correct genetic defects that cause human disease. Since 11% of inherited human genetic diseases are caused by premature stop codons, nonsense suppressor tRNAs are of increasing interest for applications in tRNA therapeutics. We recognize that both synthetic biology and therapeutic applications of tRNAs will rely on nonsense and in some cases missense suppressor tRNAs, to generate novel proteins or to correct genetic defects. Thus, this Research Topic for Frontiers in Genetics features genetic code expansion and probing the role of tRNAs in translation for applications in synthetic biology and medicine.Several contributions in this special issue focus on the role and engineering of aminoacyl-tRNA synthetases and tRNAs in genetic code expansion. Research in this field has enabled the production of recombinant proteins with genetically encoded non-canonical amino acids, such as phosphoserine and N-acetyl-lysine. Jiang et al present an engineered pyrrolysyl-tRNA synthetase (PylRS), which, rather than its natural substrate pyrrolysine (Pyl), instead directly charges tRNA Pyl with a D-amino acid. Successful incorporation of D-phenylalanine analogs (DFAs) into both the superfolder green fluorescent protein and human heavy chain ferritin was demonstrated. Incorporation of D-amino acids is selected against in the endogenous translational machineries, where only L-amino acids are incorporated with high fidelity. The development of this newly evolved PylRS•tRNA Pyl pair will allow the site-directed incorporation of D-amino acids into a diverse array of recombinant proteins. Potential future application areas include using genetically programmed D-amino acids to generate optically active proteins for therapeutic applications or the evolution of novel protein functions that are inaccessible to normal cells.While significant progress has been made in engineering the aminoacyl-tRNA synthetases, such as PylRS, to expand the palebe of different proteinogenic amino acids, the engineering of tRNAs has only more recently come into focus as a major approach to optimize and tune nonsense and Their overall goal was to use sense codons rather than stop codons, to expand the genetic code with non-canonical amino acids. Anticodons with an adenosine in the wobble positions are often modified to inosine, allowing for expanded decoding of multiple codons allowing the I34containing tRNA to base pair with U, C, or A at the wobble position. Since this fact has important implications for the fidelity and specificity of sense codon reassignment, the authors evaluated the missense suppression efficiencies of 15 of the 16 possible orthogonal tRNAs with A34 anticodons and found that the I34 modification only occurred in a minority of the engineered
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".