All life we know on Earth writes its own genetic instructions in DNA with the exact same four-letter alphabet: A (adenine), T (thymine), C (cytisine) and G (guanine). But what if there was a DNA with double the letters? Not science fiction: it already exists, it’s called Hachimoji DNA (“eight letters” in Japanese), and was built in a laboratory. Unlike traditional deoxyribonucleic acid, it forms four pairs of nitrogenous bases in total: the two natural pairs (AT, CG) that make up our genome are flanked by two more synthetic ones (BS, PZ).
The most recent news, reported in the study “Structural basis of transcription of the hachimoji eight-letter alphabet by E. coli RNA polymerase” published on Nature Communicationsis that this synthetic DNA was read and transcribed into RNA by a bacterial enzyme, theRNA polymerase Of Escherichia colithe same type of molecular machine that each cell uses to “read” its genes. This could be an important step towards functioning artificial life systems, and could open up scenarios ranging fromdigital data storage at the search for life forms extraterrestrial based on chemistry different from ours.
From 4 to 8 bricks: the stable structure of Hachimoji DNA
The DNA present in all our cells is a double helix “ladder” whose rungs are made up of base pairs which are held together through hydrogen bonds (weak electrostatic attractions between hydrogen atoms and other atoms): theadenine (A) always pairs with the thymine (T), the cytosine (C) always with the guanine (G).
In 2019 a team led by Steven Benner and Shuichi Hoshika (Foundation for Applied Molecular EvolutionFlorida) posted on Science the creation of a system a eight letters: four synthetic bases are added to the four natural bases, called P, Z, B And Swhich mate respectively P with Z And B with S. To ensure that these bases recognize each other uniquely, the researchers engineered their structure by rearranging the arrangement of hydrogen donor and acceptor atoms.
Using X-ray crystallography, the researchers demonstrated that these artificial molecules they do not deform the architecture of the double helixkeeping the proportions of the standard DNA intact. This structural stability is fundamental and responds to the principle of the “aperiodic crystal” theorized by Erwin Schrödinger in 1944: to conserve biological information, a molecule must be able to freely vary its sequence while maintaining a rigorous and regular geometric framework. If the synthetic bases had distorted the helix, DNA would have become unstable and at all unreadable for cellular enzymes. By preserving its exact geometry, however, this artificial system has proven to be compatible with the mechanisms of biology that we already know.
The new studies: transcription via E. coli
Until now, the Hachimoji alphabet had only been successfully transcribed by the bacteriophage RNA polymerase T7a very simple single subunit enzyme. The Cellular RNA polymerases that transcribe the genes of bacteria, plants and animals are multi-subunit complexes with much more stringent quality control mechanisms.
A study published in 2026 on Nature Communications from Dong Wang’s group (University of California San Diego)in collaboration with Benner himself, demonstrated that the RNA polymerase of E. coli is capable of transcribe the P:Z pair efficientlythus adding a second piece (after the B:S pair, already characterized in a previous work by the same group) to the transcription of the entire eight-letter alphabet by a cellular enzyme. Through structures obtained with electronic cryoscopy (cryo-EMa technique that allows “photographing” frozen proteins at near-atomic resolution), the researchers observed that the P:Z pair, once loaded into the active site of the enzyme, induces the same conformational change that is observed when the enzyme incorporates natural bases. In practice, for the polymerase, P and Z are almost indistinguishable from a normal G:C pair.
The base Z, however, due to a nitro chemical group (-NO₂) tended to lose a proton and take on a shape that mimics the cytosinemistakenly pairing with the guanine natural. To correct this flaw, the team synthesized a variant call Z*in which the nitro group is replaced by a carboxamide group. This intervention made the loss of the proton much more unlikely by reducing pairing errors.
Data storage and spatial research: what is it for
All very curious and interesting but what could be the real applications of Hachimoji DNA? The authors of the research explain that the most concrete applications are found in the world of aptamers: small molecules of DNA or RNA capable of binding with great specificity to a target, including proteins, a bit like an antibody does. The six- and eight-letter alphabet has already made it possible to develop these structures (AegisBinders) with binding capacities superior to those achievable with four-letter DNA alone. Previous work cited by Wang’s team describes six-letter aptamers designed to selectively target liver cancer cells. Among the main future goals is the translation from Hachimoji RNA into proteins.
Furthermore, a richer genetic alphabet means being able to encode more information in the same physical space. With four additional letters, the number of possible sequences grows, which makes this alphabet a candidate for high-density data storage. Finally, if stable genetic information readable by a cellular enzyme can be based on a chemical alphabet different from that of Earth, then the criteria with which we look for traces of life elsewhere in the universe may not be limited to looking for “our” DNA.
