An Artificially Expanded Genetic Information System (AEGIS) is a transformative concept in biotechnology and genetic engineering. It involves creating or modifying genetic systems to expand their capabilities beyond natural limits, offering hope for revolutionary advancements. Modifications may include [1] the additon of new genes, [2] designing novel genetic pathways, or [3] engineering organisms to produce new types of proteins or metabolites.
Applications for the AEGIS system are:
[1] Synthetic Biology: AEGIS in synthetic biology promises enhancements in the design and construction of new biological building blocks. Also, novel devices and systems, such as redesigning existing natural biological systems for other purposes, will be possible.
[2] Genetic Engineering: Genetic engineering aims to enhance or modify the genetic makeup of organisms to improve their performance, yields, or capabilities. An example is a genetically modified crop with new traits like drought resistance.
[3] Biotechnology Applications: The development of organisms with new or improved functionalities enabling applications in medicine, agriculture, or industrial processes.
The idea behind AEGIS is to push the boundaries of what biological systems can do by expanding their genetic information and capabilities artificially. This can lead to innovative solutions in various fields, but it also underscores the importance of considering safety, ethics, and environmental impact, urging us to be responsible and mindful in our pursuits.
The Benner group developed the artificially expanded genetic information system (AEGIS). Like a DNA polymer, the AEGIS system utilizes a biopolymer with twelve (12) building blocks. AEGIS allows the attachment of functional groups for the development of enhanced artificial polymer systems with binding and catalytic functions.
In AEGIS, nucleotides utilize Watson–Crick pairs by combining hydrogen bond donor and acceptor groups to form additional orthogonal nucleobase pairs. These newly developed nucleic acids resemble natural nucleotides in size, shape, and pairing geometries. However, they are independently replicable and do not interfere with DNA double helix structures.
| 
|
| Figure 1: Watson-Crick Pairs for C:G and T:A pairs |
| 
|
| Figure 2: Watson-Crick Pairs for Z:P and S:B pairs |
| 
Z | 
P |
| Figure 3: Example of AEGIS phosphoramidites. |
The heterocycles used in the AEGIS system are instrumental in the creation of novel base pairs. They rearrange hydrogen donors and acceptors of standard bases to implement additional hydrogen bonding patterns, as demonstrated by the Z:P and S:B base pairs (Figure 2). These novel base pairs are orthogonal to C:G and A:T base pairs, a significant achievement of the AEGIS system.
Recently, Benner’s research group solved the structure of the E. coli multi-subunit cellular RNA polymerase (RNAP) recognizing unnatural nucleobases in a six-letter expanded genetic system (Figure 4).
|  |
| Figure 4: Electron microscopy based structural model of E. coli DNA-directed RNA polymerase transcription elongation complex bound the unnatural dB-STP base pair in the active site (8SY7; Oh et al. 2023). |
This structure validates the design philosophy for AEGIS unnatural base pairs. The solved structure highlighted the importance of Watson-Crick complementarity needed for the design of AEGIS base pair recognition.
Selected References
Benner SA, Hutter D, Sismour AM. Synthetic biology with artificially expanded genetic information systems. From personalized medicine to extraterrestrial life. Nucleic Acids Res Suppl. 2003;(3):125-6. [PubMed]
Benner, S.A. (2004). Chemistry. Redesigning genetics. Science 306, 625–626.
Benner SA, Ricardo A, Carrigan MA. Is there a common chemical model for life in the universe? Curr Opin Chem Biol. 2004 Dec;8(6):672-89. [PubMed]
Benner, S.A., Kim, H.-J., Merritt, K.B., Yang, Z., McLendon, D.C., Hoshika, S., and Hutter, D. (2015). Next-generation DNA in pathogen detection, surveillance, and CLIA-waivable diagnostics. SPIE Digital Library 9490, 94900K-94900K – 6.
Biondi, E., Lane, J.D., Das, D., Dasgupta, S., Piccirilli, J.A., Hoshika, S., Bradley, K.M., Krantz, B.A., and Benner, S.A. (2016). Laboratory evolution of artificially expanded DNA gives redesignable aptamers that target the toxic form of anthrax protective antigen. Nucleic Acids Res. 44, 9565–9577. [PMC]
Biondi E, Benner SA. Artificially Expanded Genetic Information Systems for New Aptamer Technologies. Biomedicines. 2018 May 9;6(2):53. [PMC]
Karalkar N.B., Hoshika S., Laos R., Shaw R.W., Matsuura M., Fajardo D., Moussatche P. Alternative watson-crick synthetic genetic systems. Cold Spring Harbor Perspect. Biol. 2016;8 doi: 10.1101/cshperspect.a023770. [PMC]
Oh J, Shan Z, Hoshika S, Xu J, Chong J, Benner SA, Lyumkis D, Wang D. A unified Watson-Crick geometry drives transcription of six-letter expanded DNA alphabets by E. coli RNA polymerase. Nat Commun. 2023 Dec 12;14(1):8219. [PMC, pdb/8SY7]
Richards NGJ, Georgiadis MM. Toward an Expanded Genome: Structural and Computational Characterization of an Artificially Expanded Genetic Information System. Acc Chem Res. 2017 Jun 20;50(6):1375-1382. [PMC]
Sismour AM, Benner SA. Synthetic biology. Expert Opin Biol Ther. 2005 Nov;5(11):1409-14. [PubMed]
---...---
" Bio-Synthesis provides a full spectrum of high quality custom oligonucleotide modification services including artificial nucleic acids, 5'-triphosphate and back-bone modifications, conjugation to fatty acids, biotinylation by direct solid-phase chemical synthesis or enzyme-assisted approaches to obtain artificially modified oligonucleotides, such as BNA antisense oligonucleotides, mRNAs or siRNAs, containing a natural or modified backbone, as well as base, sugar and internucleotide linkages.
Bio-Synthesis also provides biotinylated mRNA and long circular oligonucleotides".
---...---