Synthetic Nucleic Acids: Beyond DNA and RNA

Synthetic biology is such a wide-ranging and multi-disciplinary field that it seems like every new paper sends me into a new area of science that I hadn't considered before. The latest issue of Science features a paper¹ on synthetic nucleic acids, completely new molecules capable of information storage just like DNA and RNA, dubbed xeno-nucleic acids, or XNAs.

There are lots of reasons to understand the limits of biological-or chemical-information storage. It is truly wondrous that the phenomenon exists at all; our genome is quite an awe-inspiring 46-molecule collection (for each chromosome is, at heart, an enormously long but unbroken molecule of DNA). All life, at least as we know it, uses DNA or RNA for storing and retrieving genetic information. We know for certain that DNA was not the first information storage molecule, since DNA is completely reliant on a protein copying mechanism that is far too complicated to have been present at the origin of life. RNA has been suggested as a potential first molecule, since we recently discovered that RNA molecules can hold a dual information storage and catalytic role.

However, there is no way to know directly what the first molecule of life was. The fact that DNA and RNA alone exist in life today still leaves the possibility that they took over, following in the footsteps of earlier information storage molecules, which perhaps could have formed more readily in the prebiotic environment of early Earth. Fundamental science aside, though, studying novel nucleic acids is important for biotechnology. Synthetic biochemistries might allow for synthetic organisms or treatments that don't interfere with the system of genetics shared by all of life. As a commentator² suggested, antisense XNAs could be used to silence RNAs of a complementary sequence. Silencing faulty genetic transcripts could remedy a wide range of genetic diseases, including cancers. And, unlike regular RNA, XNAs are not targeted by cells for degredation.

What the researchers did was build nucleic acids with the same four bases-A, C, T, and G-but with different sugars. Nucleic acids all share an alternating sugar-phosphate backbone with bases sticking out from the sugars (see figure by Watson and Crick). Traditionally, synthetic nucleic acids like this have had to be chemically synthesized. Enzymes in nature deal with DNA and RNA, not XNAs, and we aren't anywhere close to designing enzymes from scratch-for any purpose. However, the authors were able to evolve enzymes that come halfway: copying XNA into DNA and DNA into XNA. An intermediate PCR step copies DNA into more DNA, so that by the numbers all the copying occurs in DNA, but you have XNA at both the beginning and the end (see figure). It's a bit of a messy patch, but it's a huge step forward, especially since they tested it on six different XNAs (that is, six different varieties, all with a different sugar).

A copying mechanism is important, but for XNAs to be useful in understanding the origin of life they must also be capable of catalytic properties. After all, if they can't catalyze any reactions, why not just stick with RNA as the original replicator? The authors attempted to evolve XNA aptamers, XNA molecules that bind to a substrate, using HNA (one of the six). They were able to select for binding to several substrates with good specificity (they were able to pick out their target even within the hustle and bustle of a cell culture).

This paper shows that an alternative genetics can be maintained by adapting existing enzymes. Although we can't yet copy XNAs directly, it isn't a big leap from the DNA intermediate to direct copying. The fact that this patchwork copying mechanism ranged in efficiency 95% to 99.6% (depending on the XNA) shows recombinant enzymes can be of surprisingly high fidelity (though of course these still pale in comparison to the 1-in-a-billion error rate of human DNA polymerase).

As we learn more about XNAs, we can both answer fundamental questions about biochemistry, such as how an alternative genetics might work, and come up with new treatments for genetic diseases that target faulty RNAs directly.

A Tangent

Joyce's review² of the article ends on an odd note that stands out as drastically different in tone and in my view unprompted within the context of the article:

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." 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.

Admittedly, I have never read 2010, but the implication seems to be that certain research is too close for comfort to an area that's too dangerous to even ponder. What exactly does "potential to harm our biology" mean? Cancer alone has an enormous potential to harm our biology-in fact it has gone far beyond potential because many people's biology has been brought to its knees by cancer! Let's not lose sight of the bigger picture here. Sure synthetic biology has risk, but the problems it promises to address are so pervasive and devastating that to limit our inquiry based on arbitrary, unfounded proclamations (reminiscent of Eden's Tree of Knowledge, really!) is unacceptable, and I was disappointed to read that naïve appraisal in the pages of Science. Risk analysis for synthetic biology should be dynamic, changing alongside our understanding, not arising out of blanket declarations.

Image Credits: Fig. 1 from Watson, J. D. & Crick, F. H. C, Nature 171, p. 964; Rendered by me, but based on part C of the Fig. in ref. 2.

References:

1. Pinheiro, V. B. et al. Synthetic Genetic Polymers Capable of Heredity and Evolution. Science 336, 341-344 (2012).

2. Joyce, G. F. Toward an Alternative Biology. Science 336, 307-308 (2012).