‘There are four bases, adenine, thymine, cytosine and guanine.’ This phrase has been directly lifted from the Pearson Edexcel IGCSE Biology textbook, and a simple fact that we can learn to reach that 9. This fact holds true for A-level syllabi where we learn about interactions between these purines and pyrimidines to form nucleotides with 5-carbon sugars and phosphate backbones. Yet, recent research has shown that different genomic systems many have existed previously (and perhaps even now elsewhere in the universe.) An article in Nature announced creating a bacterium with 6 bases, while in Science Cambridge researchers announced 6 artificial genetic polymers known as ‘Xeno nucleic acids’ or XNAs. This leads us to question whether our search for DNA/RNA-based life forms are futile, and whether 4-base (deoxy)ribose nucleic acids as a genetic code was just a fortunate ‘stupid design’ (Steven Benner) that nature stumbled upon at the very start of life.

Six-base nucleic acids

Olena Shmahalo/Quanta Magazine

For decades, researchers have been trying to create a nucleotide that incorporates an extra base pair – i.e. two extra bases. However, the construction of unnatural systems is difficult – more bases generally made structures more susceptible to misfolding (and thus very few replicated successfully) or weren’t adopted by the cells who treated these engineered nucleotides as ‘foreign.’ For example, researchers Zhang and Romesberg created new bases dNaM and dTPT3 (ignore the names), which were able to hold more genetic information in chromosomes but required the existence of packing and hydrophobic forces to hold the nucleotide together. This meant that the double-helix structure was not possible using these artificial bases, leading to a more physically unstable nucleotide.

The real breakthrough came in 2014, with the discovery of two bases which bonded using Watson-Crick pairing rules (what A-T and C-G employ). These two chemicals were 6-amino-5-nitro-3-(1′-β-D-2′-deoxyribo-furanosyl)-2(1H)-pyridone and 2-amino-8-(1′-β-D-2′-deoxyribofuranosyl)-imidazo[1,2-a]-1,3,5-triazin-4(8H)-one.

Naturally, it was called base ‘P’ and base ‘Z’

This solved the problem of instability as the helix shape retention meant negatively charged phosphates were facing outwards, while the function group in P and the nitro group in Z meant the nucleic acids could play the role of proteins and be more efficient at molecular binding respectively. So far, these engineered polymers have been shown to bind better to cancer cells and be more effective at cell signaling. In addition, it is theorized that incorporating this into RNA would allow it to ‘fold’ into more complex shapes, potentially reducing the need for protein synthesis and folding as RNA could play the same role due to its increased specificity. This would create a two-biopolymer system.

XNA and ‘thinner’ DNA

Robbie Gonzalez/Gizmodo website

‘Alien’ nucleic acids are the result of toying with not the base pairs of nucleic acids, but with the backbone structure itself. In this case, the ribose and deoxyribose are replaced with sugars containing 4 or even 7 carbon atoms! As base integrity is kept, there is currently a 95% success rate for copying XNA to DNA and back – this figure is very high for any initial experiment. So far, 6 stable variations of XNA have been synthesized, all of which can store hereditary information or serve as enzymes. So why is this discovery so useful? Perhaps one could incorporate strands of XNA into DNA or RNA nucleotides to allow for more variation in genetic variation – the fact that there are only 21 different amino acids that can be synthesized by natural means is a shortfall. Alternatively, as there are currently no naturally-produced enzymes that can break down XNA-based proteins, we could manufacture protein inhibitors and antibodies to fight pathogens, which using XNA would be more durable as they would not be broken down as quickly when recognized as foreign – enough time to perform their job.

More recently, researchers famous for toying with DNA have explored using 8 completely different molecules to create ‘thin’ and ‘fat’ DNA. This is where small bases bind to small bases, while large bases bind to large bases – going against a fundamental theory of the genetic code (large purines can only bind to smaller pyrimidines) – No significance has been found yet of this possibility.


Toying with DNA has never been more varied, until now. Carbon as the main constituent for life? Why limit ourselves to one element, when we could follow Star Trek and manufacture our own Organosilicon nucleic acids? Silicon is touted as the alternative because it is very similar to Carbon, forming 4 bonds and thus able to form long polymers. In addition, as the 2nd most abundant element silicon as a constituent for an organism’s genetic code doesn’t seem too unlikely. If only Silicon could bind with Carbon naturally, thus able to incorporate itself as the backbone of nucleotides…

Enter cytochrome C. This protein, discovered by the winners of the Caltech SISCA prize, naturally catalyzes the formation of silicon-carbon bonds at a minor level, yet with directed evolution (production of enzymes by artificial selection) an Iron-based enzyme has been created which is 15x as effective as enzymes manufactured by chemical means. This signifies a potential for using silicon atoms as an alternative biochemistry of life. However, silicon reactions are usually much slower than Carbon, bond energies between Si and C are weaker than C-C bonds, and in the presence of water molecules based on Si and H are quite unstable. Perhaps this idea is currently too optimistic after all, but there is still a possibility of silicon-based organisms existing on planets with different conditions – which one really hopes for.

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