Awesome post dude!  thank you :)       But I have one question.. Do any of these XNA's stimulate immune response from our body?  Because that is one of the major challenges for the aptamer application in humans.


On Saturday, 21 April 2012 02:15:03 UTC+5:30, Tom Randall wrote:

Some real science fiction, from today's issue of Science. Hope most of it comes through, graphics may not.

Science 20 April 2012:
Vol. 336 no. 6079 pp. 307-308
DOI: 10.1126/science.1221724

• Perspective

Evolution

Toward an Alternative Biology

1. Gerald F. Joyce

+ Author Affiliations

1. Departments of Chemistry and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Related Resources

In Science Magazine

• Report Synthetic Genetic Polymers Capable of Heredity and Evolution

  • Vitor B. Pinheiro et al.

  Science 20 April 2012: 341-344.

Genetics provides a mechanism for molecular memory and thus the basis for Darwinian evolution. It involves the storage and propagation of molecular information and the refinement of that information through experience and differential survival. Heretofore, the only molecules known to be capable of undergoing Darwinian evolution were RNA and DNA, the genetic molecules of biology. But on page 341 of this issue, Pinheiro et al. (1) expand the palette considerably. They report six alternative genetic polymers that can be used to store and propagate information; one of these was made to undergo Darwinian evolution in response to imposed selection constraints. The work heralds the era of synthetic genetics, with implications for exobiology, biotechnology, and understanding of life itself.

XNA analogs of nucleic acids.

DNA is composed of a deoxyribose–phosphate backbone and the standard four bases (A). Pinheiro et al. show that through transcription using engineered polymerases, DNA can be copied to various XNAs that are analogs of the DNA structure (B). Black, red, and green balls indicate carbon, oxygen, and fluorine atoms, respectively. These XNAs can in turn be reverse transcribed to DNA using other engineered polymerases. The current XNA amplification process relies on PCR amplification of a DNA intermediate (C).

These first steps outside of biological genetics are modest ones, involving XNA molecules, where NA stands for nucleic acid and X refers to the sugar moiety or its substitute. The compounds are analogs of biological nucleic acids (see the figure, panel A). However, the sugar or sugar-like component is not the ribose found in RNA or the deoxyribose found in DNA. It has been replaced by a different five-carbon sugar (arabinose in ANA, 2′-fluoroarabinose in FANA), a four-carbon sugar (threose in TNA), a "locked" ribose analog in LNA, or a six-member ring structure (cyclohexene in CeNA, anhydrohexitol in HNA) (see the figure, panel B).

The study of XNAs has been inspired by the question of what was the first genetic polymer of life on Earth. Perhaps this was RNA, but it may have been a simpler structure that was more readily accessible through prebiotic synthesis (2). TNA and glycol nucleic acid (GNA) are prime candidates (3, 4). Another inspiration for the study of XNAs is their application as antisense agents that bind to and thereby inhibit the function of biological RNAs. All six XNAs studied by Pinheiro et al. bind to complementary RNA and DNA and are resistant to degradation by biological nucleases. Finally, construction of genetic systems based on alternative chemical platforms may ultimately lead to the synthesis of novel forms of life. For that goal to be realized, the XNA must be able to catalyze its own replication, without the aid of any biological molecules, and thus be capable of undergoing Darwinian evolution in a self-sustained manner.

Pinheiro et al. have made great progress in showing that various XNAs can function as synthetic genetic polymers, but they have not yet realized a synthetic genetic system. In their system, the XNAs are replicated by reverse-transcribing them to DNA, amplifying the DNA using PCR, and then forward-transcribing the DNA back to XNA (see the figure, panel C). Each step uses a polymerase; amplification takes place with DNA. Another recent paper showed the storage and propagation of genetic information in TNA, but there, too, amplification occurred with DNA (5).

The key innovation of Pinheiro et al. is their use of sophisticated protein engineering techniques to develop variant polymerases that are adept at copying information between XNAs and DNA. They show that XNA polymers containing more than 70 subunits and having almost any sequence can be copied to and from DNA, with an average fidelity per subunit ranging from 95% (for LNA) to 99.6% (for CeNA). These attributes are sufficient to carry out the directed evolution of functional XNA molecules. The authors demonstrate this process for HNA polymers, which they evolved in the laboratory to obtain functional molecules (aptamers) that bind tightly and specifically to a particular RNA or protein target.

Pinheiro et al. give some hint of what will come next. They have begun to apply the same protein engineering techniques to develop polymerases that can copy an XNA to its own complement or copy information between two different XNAs. So far, both FANA and CeNA have been copied to their own complement and CeNA has been copied to HNA, but these processes are much less efficient than copying information between XNA and DNA.

Future studies are likely to yield improvements of the various XNA-to-XNA copying reactions. It also seems only a matter of time before there will be the first reported "XNAzyme"—a catalyst composed of XNA rather than protein or standard nucleic acid. A key aim will be the development of XNAzymes that catalyze the templated joining of XNA oligomers and ultimately the polymerization of XNA monomers. Synthetic biology studies of XNA may never catch up to those involving RNA because the former require more challenging preparative and analytical procedures and do not benefit from the technical infrastructure that supports RNA research. However, the comparative biochemistry of various XNA systems is itself a worthy pursuit, enabling one to investigate principles of macromolecular structure, molecular recognition, and catalysis across a series of related chemical polymers.

Another important reason to pursue the development of functional XNAs is to obtain compounds with potential applications in materials science, molecular diagnostics, and therapeutics. Nucleic acid aptamers have been widely adapted for these purposes, but because RNA and DNA are susceptible to biological nucleases, they must be modified to withstand exposure to the natural world. XNAs are unnatural and would pass through the biosphere unscathed. The benefits of their unusual chemical properties must be weighed against their greater cost, both literally and with regard to operating in the uncharted waters of XNA biochemistry.

As one contemplates all the alternative life forms that might be possible with XNAs and other more exotic genetic molecules, the words of Arthur C. Clarke come to mind. In 2010: Odyssey Two, HAL the computer tells humanity: "All these worlds are yours" but cautions: "Except Europa. Attempt no landings there" (6). Synthetic biologists are beginning to frolic on the worlds of alternative genetics but must not tread into areas that have the potential to harm our biology.

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