Orthogonal Central Dogma: A Platonic ideal

Synthetic genes and genetic programs rely on host central dogma process i.e. replication, transcription and translation for propagation and expression.

Synthetic biologists therefore write genetic programs with the host organism in mind and accept both the rigidities and regulatory complexities associated with host central dogma systems. This dependency poses two challenges;

  1. Transfer of developed genetic program from model organism to suitable host.
  2. Functions that require reengineering of host central dogma processes are inaccessible e.g. rapid mutagenesis, evolution or repurposing translation.


Orthogonal system: A network of (engineered) components (for example, proteins, RNAs, DNAs, and small molecules) that interact with each other to achieve a specific function without impeding or being impeded by the native functions of the host cell. The components making up an orthogonal system are characteristically strongly connected to each other but weakly connected to the rest of the cell, except in ways strategically chosen by the biological engineer.

Natural systems such as mitochondria and chloroplasts already have dedicated replication, transcription, and translation machinery, suggesting that such systems are possible, acting as potential platforms for further engineering.

An orthogonal central dogma needs numerous components, and each one carries potential undesired interactions with the rest of the cell. Although direct molecular interactions with host components can be engineered away, such interactions may be difficult to identify in the first place. Furthermore, the demands that an orthogonal central dogma may place on the rest of the cell’s resources is a challenge that will need to be addressed. Therefore, the extent to which such large orthogonal networks can be constructed is uncertain.

Ref: https://www.nature.com/articles/nchembio.2554

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