New evidence by Prof. Thomas Carell's group elucidates the possibility of an ‘RNA-peptide World’
How did life begin on Earth is one of the greatest mysteries in all of science. While the famous evolutionary biologist, Charles Darwin, suggested life might have evolved through a small pool of concentrated chemicals, known as primordial soup, it is still unknown how the building blocks of life— RNA, DNA, proteins, and lipids — interconnected to form self-replicating cells.
One concept put forth in the 1960s by Carl Woese, Francis Crick, and Leslie Orgel proposes that early life forms used RNA alone for the storage of genetic material. This meant, that the early RNAs (single-stranded Ribonucleic Acid) were stable and developed catalytic functions. Later, as life became complex, more stable Deoxyribonucleic Acids or DNAs took over to become the genetic material and proteins evolved catalytic functions. This theory was coined in 1986 as the ‘RNA World Hypothesis’ by a molecular biologist, Walter Gilbert.
However, the latest work published in Nature by Thomas Carell, Professor of Organic and Biomolecular Chemistry, and his colleagues provide evidence that seemingly is in conflict with this possibility. “Something is not fitting”, says Prof. Carell — the idea that self-replicating RNA molecules existed and by mutations created diversity, and, as better replicators appeared, they finally gained catalytic functions seems imperfect. The main evidence supporting this claim is that until today scientists have not found these RNA replicators and were never successful in making them.
Secondly, the amino acids (that link to form protein strands or peptides) are as old as the nucleosides (that form RNA or DNA strands). “Nucleosides are so much more complex. By their chemical structure what I would argue is the first thing that was formed were the amino acids and then came nucleosides”, explains Prof. Carell adding that it seems wrong to assume that while Nucleosides formed strands, amino acids were doing nothing, only to be discovered as the better catalysts a couple of hundred million years later.
“If we assume the nucleosides and amino acids were present from the beginning as accompanying molecules, then potentially they formed a unit. Thus, we looked for nucleosides that contained amino acids. And, we were surprised to see that there’s a whole set of RNAs with nucleosides and amino acids combined as one molecule.”
This discovery is fascinating as it also puts an end to the age-old ‘Chicken-and-egg’ problem. Before the RNA World Hypothesis, scientists have argued about what existed first — a peptide or the RNA — and how was their connection made.
“What we have shown is that we believe there were chimeric molecules, like Siamese twins, where one part was the RNA and the other was the peptide. And thus, the whole molecule had two parts — a coding function (which was in RNA that could potentially replicate) and the phenotypic function associated with the peptide. As this molecule kept growing, the peptide and the RNA got larger, and all of a sudden these large structures linked by non-covalent bonds separated into RNAs and proteins”, adds Prof. Carell, highlighting the scenario of a chimeric RNA-Peptide World.
As a scientist working on the interface between chemistry and biology, Prof. Carell points out how difficult it is to keep his students, mostly chemists, motivated to work on this theory. “Many of my students say they want to work on chemistry and medicine questions but not on this strange philosophical theory towards finding answers to how life evolved. But then I proposed this project to Dr. Luis Escobar, a postdoc in my lab, who very meticulously optimised the conditions and made it work, only to be followed by another Ph.D. student Felix Müller who is now the first author of the published study. And now, for the very first time we are able to chemically synthesise these RNA-peptide chimeras, which about 10 years ago was not even possible”, says Prof. Carell. That explains 160 pages of supporting information added to the paper as it was important to establish a completely new synthesis of molecules that nobody has ever made before.
The previous studies from the group have also tackled the origin of purine and pyrimidine nucleosides and now, Prof. Carell is all set to establish a new Chemical Biology Institute at Ludwig Maximilian University (LMU) of Munich dedicated to studying the chemistry of epigenetic programming in DNA and RNA.
For someone who had offers to join the best institutes and universities in the world including the ivy league schools, Prof. Carell talks about the factors that made him stay at LMU. He adds, “I am still proud of having offers from such prestigious institutes as there are very few foreigners who can say they could become full-professors at such institutes. However, transitioning at a new place didn’t work out for my group. Frankly, I love LMU and what it has offered me. Of course, I will not compare it with the Harvard; but if Harvard is the best school in the US, my university is the best we got in Germany. They have given me good funds, about 45 million Euros to make a new institute and a lot more".
This is a Behind-the-discovery article featuring the researchers’ vision behind the experiments and conversations around the academic conditions that aided this study.