Evolution of catalytic RNAs, and the Origin of Life
Ph.D., , University of Technology Darmstadt, Germany
BS, , LMU Munich, Germany
Awards and Academic Honors
NRSA fellowship from the NIH
Postdoctoral award from the German Research Council (DFG)
Postdoctoral research, Whitehead Institute, Cambridge, MA
The Muller lab is interested in catalytic RNA molecules (ribozymes). We focus on two areas, ribozymes in the origin of life and ribozymes as therapeutic agents. To obtain these ribozymes we either design ribozyme variants based on existing ribozymes, we evolve improved versions of existing ribozymes, or we select new ribozymes from random sequence.
Ribozymes and the origin of life
Life probably originated via an evolutionary stage called the RNA world. In this scenario, RNAs served both as genomes and as catalysts, whose functions were later mostly overtaken by DNA and by proteins. We are trying to generate a self-replicating system of catalytic RNAs, mimicking an RNA world. If we were able to generate such a system, it could show us how an RNA world could function, and how an RNA world was able to evolve into today's DNA/protein life forms. Such a system would allow us to analyze its evolution on the molecular level because its small genome could be sequenced at every single generation. Because this system would evolve by itself it would also show us what alternate paths early evolution could have taken.
Ribozymes for therapeutic applications
Most ribozymes that were developed for therapeutic applications are aimed at the specific degradation of target mRNAs. We are using a different approach (pioneered by Bruce Sullenger, Duke University) that is aimed at repairing mutations in mRNAs. It uses group I intron ribozymes to replace the mutated portion of the mRNA with a "healthy" sequence. This approach has the advantage that it could be used for the treatment of loss-of-function mutations, and that the repaired mRNA remains regulated by endogeneous mechanisms. However, these ribozymes have not been used in clinical application, partially because of their low mRNA repair efficiency in vivo. We are improving the efficiency of these ribozymes, aiming for efficiencies that are sufficient for therapeutic applications.
Primary Research Area
- Meluzzi D, Olson KE, Dolan GF, Arya G, Müller UF, "Computational prediction of efficient splice sites for trans-splicing ribozymes.", RNA, 2012, 3, 590-602
- Olson KE, Müller UF, "An in vivo selection method to optimize trans-splicing ribozymes.", RNA, 2012, 3, 581-9
- Yao C, Moretti JE, Struss PE, Spall JA, Müller UF, "Arginine cofactors on the polymerase ribozyme.", PLoS One, 2011, 9, e25030
- Yao C, Müller UF, "Polymerase ribozyme efficiency increased by G/T-rich DNA oligonucleotides.", RNA, 2011, 7, 1274-81
- Müller UF, "Evolution of ribozymes in an RNA world.", Chem Biol, 2009, 8, 797-8
- Müller UF, Bartel DP, "Improved polymerase ribozyme efficiency on hydrophobic assemblies.", RNA, 2008, 3, 552-62
- Müller UF, "Re-creating an RNA world.", Cell Mol Life Sci, 2006, 11, 1278-93
- Müller UF, Bartel DP, "Substrate 2'-hydroxyl groups required for ribozyme-catalyzed polymerization.", Chem Biol, 2003, 9, 799-806
- Müller UF, Göringer HU, "Mechanism of the gBP21-mediated RNA/RNA annealing reaction: matchmaking and charge reduction.", Nucleic Acids Res, 2002, 2, 447-55
- Müller UF, Lambert L, Göringer HU, "Annealing of RNA editing substrates facilitated by guide RNA-binding protein gBP21.", EMBO J, 2001, 6, 1394-404