My group's interest in the ribosome dates back more than 25 years. As a postdoc, Arun Malhotra developed methodology for combining a wide range of experimental data on RNA-protein interactions – especially footprinting, and cross-linking – with the low-resolution density maps then available from electron microscopy and the protein map from neutron diffraction, to generate the first quantitative model for the structure of the small ribosomal subunit.


   Our investigations into the evolution of the ribosome began when Robin Gutell proposed that the database of rRNA secondary structures suggested the existence of a "minimal ribosome". He asked us to map his results onto the crystal structures of the two ribosomal subunits. Working with him and Rajendra Agrawal, we published the first model for the minimal ribosome; this work was led by Jason Mears, who was then a graduate student in my group. Shortly after, Agrawal's group obtained a cryo-EM map of the large subunit of the mammalian mitochondrial ribosome – which is very close to a minimal ribosome – leading to a jointly refined improved model.

   But things got really interesting when Loren Williams invited me to join his efforts at teasing out the origin of the ribosome. He and Chiaolong Hsiao had carried out an analysis of the structure of the large ribosomal subunit, examining things in successive layers outward from the peptidyl transferase site – a process they called "peeling the onion". The resulting model for ribosomal evolution had many features in common with our minimal ribosome, and with others, particularly the hierarchichal model for the evolution of the 23S rRNA, developed by Sergei Steinberg. Loren recruited others, including Nick Hud and Roger Wartell, and we had five exciting years, supported by the NASA Astrobiology Institute.

   Among the most exciting results of that work were our observation that Mg2+, which is critical to the structure and catalytic activities of many RNAs, can be replaced by Fe2+. Soluble ferrous iron was abundant in the oceans before the great oxidation event that followed the origin of photosynthesis. Our first advance, led by Shreyas Athavale and Anton Petrov, showed that, in an anoxic environment: Fe2+ binds to RNA more tightly than Mg2+; Fe2+ promotes RNA folding; and the catalytic activity of ribozymes is not adversely affected – and is sometimes enhanced – when magnesium is replaced by iron. (link). This result has significant implications for prebiotic evolution, given the abundance of Fe2+ in the primordial oceans. The second discovery, led by Chiaolong Hsiao, was that RNA-Fe2+ complexes can catalyze electron transfer. (link). This observation that RNA can support redox reactions also has profound implications for those who believe in the strong form of the RNA World Hypothesis, which holds that RNAs had responsibility for both the catalytic and replicative activities of macromolecules in the era before the appearance of the complete DNA-RNA-protein world.