Niko McCarty
Jan 30 · 4 min read

How a molecular machine four billion years in the making was modified to imbue cells with unnatural abilities.

Four billion years ago, a single-celled organism floated in the primordial soups of early earth. This ancient organism already had many of the makings of modern life forms, including a functional ribosome, the dynamic, nanoscopic machine that makes the thousands of unique proteins that cells need to survive.

The ribosome, a brilliant macromolecular machine that decodes mRNA messages to produce proteins. From https://pdb101.rcsb.org/motm/121

The ribosome reads an mRNA message that direct the positions of specific building blocks in the final protein polymer, a process known as translation. Two separate ribosomal subunits, the large and the small, come together to decode these messages. The catalytic activity of the ribosome is derived from ribosomal RNA sequences residing in each of the subunits — in the large subunit, a strand of RNA catalyzes the peptide bonds between amino acids, while the small subunit contains an RNA that decodes the precise position in the mRNA message to begin translation. The process of translation is such a delicate dance that it has remained relatively unaltered for nearly four billion years and took scientists several decades to decipher. Solving the structure of the ribosome and its milieu of interactions with other cellular components earned Venki Ramakrishnan, Thomas Steitz and Ada Yonath the 2009 Nobel Prize in Chemistry.

Since its discovery, scientists have sought to modify the ribosome, expanding its capabilities to synthesize not just proteins, but also new types of molecules. This effort has been hindered, in large part, because of the conserved nature of this molecular machine — even a minor modification to its structure could prove disastrous, killing off unfortunate organisms in the process. Consequently, efforts to evolve the ribosome, especially the peptidyl transferase center, have proven challenging because modifications in this region typically prevent the large and small subunits from interacting with one another properly. Until now.

Scientists from Cambridge University have reported the first ribosomes capable of synthesizing polymers, a feat impossible for natural ribosomes throughout the course of cellular evolution. The results were reported in the December issue of Nature.

By ‘stapling’, or linking, the ribosomal RNA sequences from the large and small subunits together, the team managed to create ribosomes that no longer required separate subunits to read an mRNA message. The experiment was not simple — many of the tested subunit linkers abolished ribosomal activity. One of the tested variants, however, had high activity and was used to functionally link the two subunits together into a single structure.

Schmied et al. then repeatedly carried out directed evolution on the stapled ribosomes — a fine-tuning process in which the stapled ribosomal structure gradually changes — using a process developed by Frances Arnold. This method for ‘test-tube evolution’ won Arnold the 2018 Nobel Prize in Chemistry.

The team continued their work by introducing the evolved, stapled ribosomes into living cells and entirely replacing the natural ribosomes. This marks the first time that an organism possessing no natural ribosomes has been created, which was once thought to be impossible because of the highly-conserved nature of translation. The experiment resulted in functional, semi-synthetic organisms capable of using the evolved, stapled ribosomes to build polymers not found anywhere in nature, including proteins with highly repetitive proline sequences.

Interior of the Laboratory for Molecular Biology in Cambridge, UK. Photo by cmglee.

Engineered organisms already produce many of the medicines that we are familiar with, including insulin and erythropoietin, a protein-based medicine that helps patients with anemia or kidney disease rebuild pools of red blood cells. Jason Chin, a professor at Cambridge University’s Laboratory for Molecular Biology and leader of the research group behind the study, aims to use these modified ribosomes to create synthetic organisms that can also produce advanced nanomaterials and medicines. Since the ribosome reads mRNA messages — and these messages can be readily modified by scientists in a matter of hours — these engineered ribosomes could be ‘programmed’ to build nearly infinite types of polymers.

Despite the ribosome’s largely immutable status for nearly four billion years, organisms with designer versions have been fashioned for the first time, paving the way for scientists intent on bending the molecular machine to their will.


This article is based on a scientific paper published in the December issue of the journal Nature: https://www.nature.com/articles/s41586-018-0773-z

Sources:

Schmied, W.H. et al. Nature 564, 444–448 (2018).

Ban, N. et al. Science 289, 905–920 (2000).

Clemons, W.M. et al. Nature 400, 833–840 (1999).

Fox, G.E. Cold Spring Harb. Perspect. Biol. 2, a003483 (2010).

Niko McCarty

Written by

Writer & PhD Student at Caltech. www.nmccarty.com

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