Every living cell builds proteins from just 20 standard amino acids, but a technique called Genetic Code Expansion (GCE) lets researchers add custom-designed amino acids to that toolkit, giving proteins new abilities such as switching shape in response to light or attaching chemical handles for tagging. The problem is that GCE has been too inefficient to use routinely in complex animals like mice. The researchers have already solved this for roundworms; now they aim to do the same for mouse neurons. This matters because many questions about how the brain works—and what goes wrong in disease—require precisely modifying proteins in specific neurons without disturbing their surrounding tissue. If successful, this project will turn GCE into a widely accessible tool for fundamental neuroscience. Researchers could, for example, introduce light-sensitive switches into key proteins in real time, then watch how those changes alter or restore neuron function in an intact brain. This is fundamental science: it will not directly produce a drug or device. But similar fundamental work on genetic tools—such as optogenetics—has transformed how scientists study the brain and opened entirely new avenues for understanding neurological disorders.
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Proteins and the nucleic acids DNA and RNA are the most fundamental building blocks of life and all living matter is either composed of proteins or substances produced by proteins. Proteins are chains of amino acids consisting of the same pool of 20 canonical amino acids. They are defined by the sequence of amino acids within the chain, a sequence that is encoded in DNA. The genetic code is the cipher that links the nucleotide sequence in DNA with the amino acid sequence in proteins. Genetic Code Expansion (GCE) is a ground-breaking genetic technology that gives cells the ability to expand the number of different amino acid building blocks at their disposal for making proteins. The additional amino acids, called non-canonical amino acids (ncAA), are chemically synthesized 'designer' amino acids with properties not found in nature. The addition of ncAA to the natural amino acid repertoire offers the ability to install entirely new functionalities into proteins, enabling customization for specific research goals. It is for example possible to introduce optical switches, bioorthogonal linkers to attach other molecules, or post-translational modifications. Despite the inherent power of the technology, its adoption as a research tool, especially in complex organisms like animals, has been held back thus far by low efficiency. We have recently solved this problem for the nematode worm C. elegans, where GCE is now robust, efficient, and ready for routine applications. The next step, and the objective of this proposal, is to apply our improvements to mice and make the technology accessible for fundamental and biomedical research using animals other than C. elegans. To demonstrate the broad utility of GCE across diverse animal systems our first target will be neurons in mouse brains, where numerous hypotheses related to the brain's inner workings await to be tested. We aim to use optimised GCE to develop new types of genetic tools that will allow introducing genetic modifications to neurons which can in real time be identified based on their functional or dysfunctional properties. Light mediated targeting of these select neurons will allow precise genetic changes leaving the environment of the neuron intact. This will allow testing how modification of key genes can impair or repair neuronal function in intact systems. The advancements we hope to make here are expected to overcome current efficiency barriers, making GCE technology widely accessible and unlocking its full potential for scientific research and discovery.
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