All life on Earth shares a remarkable commonality: it is written in the same chemical language. This language - the genetic code - enables cells to build proteins, the essential molecular machines of life, using the same 20 canonical amino acids as basic building blocks. Alongside DNA and a handful of other key polymers, these amino acids form the foundation of all known biology.
Today, this once-fixed code is being deliberately expanded. Scientists are now reprogramming the genetic code to include noncanonical amino acids - new chemical entities not found in nature - offering a powerful way to endow proteins and cells with entirely novel properties. This is made possible through synthetic biology, genome engineering, and clever manipulation of molecular machines that govern protein synthesis.
At the heart of this approach are custom-built enzyme-tRNA pairs known as orthogonal translation systems. These act as parallel decoding machines, introducing new amino acids into proteins in both living cells and synthetic setups. Such reprogramming enables site-specific labeling, structural probing, and even the creation of therapeutic proteins - using bioorthogonal chemistries such as click reactions to attach functional groups without interfering with native biology.
This talk will introduce the principles behind genetic code expansion, from its biochemical underpinnings to its physical implications. I will highlight real-world applications, including how these exotic amino acids serve as powerful probes in spectroscopy and microscopy, and how synthetic organisms can be designed to operate with “genetic firewalls” - built-in safety systems that isolate engineered life from the natural biosphere. Expanding the genetic code marks a shift from understanding life to engineering it. By extending nature’s toolkit, we gain control over biological function and form. This frontier invites a new generation to build systems, materials, and cells that nature never had - but now can.
References:
[1] Kubyshkin, V., Budisa, N. (2019) Anticipating alien cells with alternative genetic codes: away from the alanine world! Curr. Opin. Biotechnol. 60, 242-249; doi: 10.1016/j.copbio.2019.05.006
[2] Kubyshkin, V., Budisa, N. (2019) The Alanine World Model for the Development of the Amino Acid Repertoire in Protein Biosynthesis Int. J. Mol. Sci. 20(21), e5507; doi: 10.3390/ijms20215507.
[3] Budisa, N., Kubyshkin, V., Schmidt, M. (2020) Xenobiology: A Journey towards Parallel Life Forms. ChemBioChem, 21(16), 2228-2231; doi: 10.1002/cbic.202000141