Scientists Propose Novel Theory on Origin of Genetic Code

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Alan Herbert, Scientific Supervisor of the HSE International Laboratory of Bioinformatics, has put forward a new explanation for one of biology's enduring mysteries—the origin of the genetic code. According to his publication in Biology Letters, the contemporary genetic code may have originated from self-organising molecular complexes known as ‘tinkers.’ The author presents this novel hypothesis based on an analysis of secondary DNA structures using the AlphaFold 3 neural network.

The genetic code is the 'alphabet' that underpins the functioning of all living systems on Earth. It dictates the content of an organism's 'instructions' and how they should be interpreted. The contemporary genetic code is composed of codons, each consisting of three nucleotides. These triplets encode amino acids, which are then involved in protein synthesis. Scientists have been studying the genetic code for over 70 years, yet one of the most important questions—how it originated—remains unanswered.

Professor Alan Herbert, Scientific Supervisor at the HSE International Laboratory of Bioinformatics, has put forward a new explanation for the origin of the genetic code. In his view, during evolution, flipons—DNA sequences capable of forming secondary structures—played a key role in the development of the contemporary genetic code.

The classical DNA molecule, as described by Francis Crick and James Watson, is a double helix that twists to the right. However, scientists have discovered alternative DNA structures, including Z-DNA, which twists to the left, as well as three-stranded and four-stranded sequences, and knot-like DNA structures known as i-motifs. These unusual structures arise under specific physiological conditions, and their type depends on the sequence and arrangement of nucleotides within the flipon itself. The simplest flipons are formed from repeating nucleotide sequences, leading to the assumption that such sequences were abundant in the so-called primordial soup.

Maria Poptsova

Using DeepMind's AlphaFold 3 neural network, Alan Herbert analysed the nature of the bonds between flipons and amino acids. 'It turns out that flipons formed from two-nucleotide repeats bind very effectively to simple peptides composed of two-amino acid repeats. It is precisely this correspondence that exists in the contemporary genetic code,' comments Maria Poptsova, Head of the HSE International Laboratory of Bioinformatics.

For example, the cytosine-guanine repeat CGCGCG forms Z-DNA, and the peptide with the arginine-alanine repeat RARARA binds effectively to this sequence. In the contemporary genetic code, the CGC codon corresponds to arginine, while the GCG codon corresponds to alanine. A detailed analysis of spatial interactions reveals that the strongest connection occurs between non-overlapping triplets: CGCGCG binds to RA.

In his publication, Alan Herbert examines numerous examples of the interaction between flipons formed from short repeats and peptides made up of amino acid repeats. It has been found that reactions leading to mutual chain elongation can also occur, especially in the presence of magnesium and zinc, which act as catalysts.

According to the study author, such complexes were once formed by special components—tinkers, as François Jacob called them. In Professor Herbert's work, structures composed of flipons and peptides serve as self-replicating tinkers. Tinkers used DNA as a template for protein synthesis, while proteins, in turn, facilitated the elongation of the DNA helix. As a result, a non-overlapping triplet code emerged: the odd number of bases enables the encoding of sequences from different amino acids, while the nature of bonds between flipons and amino acids dictates that each codon corresponds to only one amino acid.

'The role of flipons as tinkers in the early stages of biological evolution offers a radically new perspective on the origins of life. It is no exaggeration to say that if this theory is experimentally confirmed, our colleague Dr Herbert deserves the Nobel Prize,' explains Poptsova. 'The discovery of interactions between flipons and amino acids, in accordance with the contemporary genetic code table, proves that the emergence of the genetic code is not an accident but a natural outcome of evolution. Nature does not create anything from scratch; it develops new mechanisms using what is already available. Nature acts like a tinkerer who, when needing to quickly create something functional—but not necessarily reliable or durable—grabs whatever is at hand.'

Alan Herbert

'Overall, the proposed scheme does not require a DNA, RNA, or peptide world to explain life’s origins,' writes Alan Herbert in his article. 'Instead, the tinkers described are agents that promote this eventuality. They arise from the simple match between low-complexity nucleotide and simple peptide polymers, using metals to catalyse their initial replication. By spiking the prebiotic soup with copies of themselves, these tinkers quite naturally evolved a non-overlapping, triplet genetic code.'

In addition to advancing our understanding of life's origins, studying tinkers could lead to the development of new technologies, including artificial self-organising systems and self-healing materials. The tinkers’ ability to combine various chemical elements can be used for directed evolution of new biomolecules.