A six-base semi-synthetic organism now multiplies

At least since the appearance of the last common ancestor of all life on Earth, about 3.5 billion years ago, genetic information is stored in a four-letter alphabet that is distributed and read as two base pairs. These are four nitrogen-carbon-hydrogen bases: adenine (A), thymine (T), cytosine (C) and guanine (G). By virtue of their chemical composition, they are tied into base pairs in a strict order, not allowing options: only AT and C-G. In such a four-fold system, all life on Earth is encoded.



The main goal of synthetic biology as a science is the creation of new life forms and new functions in existing organisms. The logical way to achieve this goal is the development of semi-synthetic organisms with an extended set of base pairs. In addition to the four bases of living nature, they may contain a pair of synthetic bases that form the third artificial base pair: XY.



Previous attempts to create such a semi-synthetic organism reached its peak in 2016 . Then geneticists managed to derive the Escherichia coli strain, which extracted the necessary synthetic triphosphates from the environment and used them to replicate plasmids with a synthetic base. It was the first case of replication of semisynthetic DNA, but still such a semisynthetic organism was not quite full-fledged. Simply storing and transferring a synthetic base pair is not enough. In order to carry some kind of benefit, it must be fully functional, that is, eventually capable of expressing proteins through RNA. And these will be proteins, which no natural form of life in the four-fold system can create.



Now biologists from the Scripps Research Institute have gone further. They created a complete semi-synthetic bacterium (pictured above) that translates an artificial base pair into mRNA with two synthetic codons and tRNA with related synthetic anticodons — and efficiently decodes them in the ribosome to include natural or non-canonical amino acids in the fluorescent protein “superfolder GFP” ( sfGFP).



In this case, sfGFP was used simply for demonstration, it is a traditional marker that is used in genetic research. Theoretically, the bacterium can encode other amino acids.



“This is the most minimal change we could make in the mechanism of nature’s work - but this was done for the first time,” commented Professor Floyd Romsberg from the Scripps Research Institute, lead author of the scientific work.









The upper part of illustration (a) shows the chemical structure of synthetic and natural base pairs. The following is a schematic representation of a gene cassette that is used to express semi-synthetic sequences. In graphs c and d, respectively, the fluorescence and growth of cells expressing sfGFP and semisynthetic tRNA. Finally, on the lower left, the western blot of lysates obtained from the last generation of these cells, shown on the rightmost elevations of the graphs c and d, and on the right, shows the relative abundance of the amino acids S, I / L and N from semi-synthetic cells



According to scientists, the results indicate that processes other than hydrogen bonding may be involved in each stage of the preservation and extraction of genetic information. It turned out that the absence of hydrogen bonds in the base pairs actually doesn’t really bother the cells: the reproduction of semisynthetic DNA still happens very successfully.



In other words, the life around us is probably not the only chemical possible. It just so happened that all life on Earth was formed from just such a single sample, but it is not at all unique.



Thus, the obtained semi-synthetic organism can simultaneously encode additional genetic information and extract it for use. “I would not call it a new form of life,” Romsberg says, “but this is the closest to the new form of life that anyone has ever been able to do. For the first time, a cell translated a protein using something other than G, C, A, or T. ”



Four natural DNA bases are able to encode as few as 20 amino acids, so all life forms on Earth are limited exclusively to these proteins. With the help of the third base pair - synthetic - the body is able to encode up to 152 new amino acids.



According to researchers, this organism should be taken as a platform for creating new life forms and functions. Theoretically, new life forms that exist in the six-dimensional system can open up completely new possibilities in medicine and pharmacology, and help in the creation of new drugs.



The American company Synthorx, Inc. specializes in searching for new drugs using the synthetic base pair X and Y.



Scientists note that the semi-synthetic form of life created by them and all others like it will not be able to live outside the laboratory walls, because appropriate chemicals must be present in the solution to reproduce the bases X and Y.



The scientific article was published on November 30, 2017 in the journal Nature (doi: 10.1038 / nature24659, pdf ).