One of the modern biologists’ greatest objectives is to figure out how to expand or modify the genetic code that governs life on Earth, in order to make new, artificial life forms.
This “synthetic biology research” is driven by the desire to understand more about the development of our natural biology and the reasoning behind it. But there’s also a very practical motivation: Cells can be used as efficient factories for making a broad array of useful molecules-;especially protein-based therapeutics, which account for an increasing share of new medicines. A cell that has an extensive genetic code can produce a wider range of medicines, and it could create them in a way that makes it much easier of developing and manufacturing them.
The realization of the grand goal of a working useful synthetic biology is still some years off. In a study that was published this week in Nature Communications, scientists have taken a major step closer to that goal by developing and demonstrating the essential components of an expanded genetic code system.
We have added the synthetic biology toolkit in order to make it easier for studies into genetic code extension.”
Ahmed Badran, PhD, Study Senior Author and Assistant Professor, Department of Chemistry, Scripps Research Institute
The genetic code that is the basis of life on Earth is used by cells to translate information that is contained in DNA and in RNA into amino-acid proteins’ building blocks. DNA and RNA molecules are chain-like molecules which encode information using an “alphabet” of four nucleotide building blocks, or “letters.” Transfer RNAs (tRNAs), which are molecular molecule, decode this information by recognising three letters at once and translating each letter into an amino-acid building block of proteins. This triplet codon system can encode 64 amino acids (4 3) However, the majority of organisms use 20 amino acids.
However, the envisioned quadruplet-based system, based on four-letter codons can encode up to 256 (4 4) distinct amino acids. Although most of these would not be present in the natural proteins, there might be slight variations on them, which would allow proteins to have more specific characteristics, such as to enhance their effectiveness and security when used as medications.
This is because the process of protein-gene translation is complex and requires many components to work together. It took millions of years to allow the system found in all living creatures on Earth to reach the current levels of accuracy and efficiency. Recent efforts to engineer whole new systems have shown promise, including quadruplet codon systems.
In the new study, Badran and his team used an evolutionary, survival-of-the-fittest, technique called directed evolution to evolve a small set of tRNAs that in principle could work in a quadruplet system. These quadruplet-tRNAs could be used to translate portions of a protein inside bacterial cell cells, according to the scientists. They were able to translate six identical quadruplet codes after each other and even four different quadruplet codens in the same protein. This was achieved at an efficiency that was just a few tenths of what is needed for a functioning quadruplet.
Badran states that even though a quadruplet code is in the early stages of methods-development and testing, it could prove to be extremely useful if it is able to work. This is particularly true in the case of allowing the easy creation of proteins that contain “noncanonical” amino acids that aren’t naturally found in proteins. These ncAAs could be utilized to provide proteins with new biological properties. They can also be used to attach harmful “warheads” to cancer drugs or to create chemical modifications to the protein.
“One could theoretically program a sequence of DNA that would be translated, in a living cell, into a protein that contains a complex set of modifications-;modifications that otherwise would be difficult or impossible to add,” Badran says.
Badran joined Scripps Research in January and was employed at Harvard and the Broad Institute of MIT during the research.
DeBenedictis, E. A., et al. (2021) Multiplex suppression by tRNA directed evolutionary. Nature Communications. doi.org/10.1038/s41467-021-25948-y.
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