Muller, Ulrich
Evolution of catalytic RNAs, and the Origin of Life
Education
2000 Ph.D.,
University of Technology Darmstadt, Germany
1995 BS,
LMU Munich, Germany
Appointments
2022 - present Professor,
UC San Diego
2014-2022 Associate Professor,
UC San Diego
2006-2014 Assistant Professor,
UC San Diego
2001-2006 Postdoctoral Researcher,
Whitehead Institute, Cambridge, MA
Awards and Academic Honors
2022-25
NASA research award
2021-26
NASA research award
2020-22
Cystic Fibrosis Foundation
2019-22
NASA research award
2018-20
Gilbert Gene Therapy Initiative
2016-19
NASA research award
2013-16
NASA research award
2011-13
Hellman Fellow
2008-11
NSF research award
2004-05
NRSA fellowship from the NIH
2001-04
Postdoctoral award from the German Research Council (DFG)
Research Interests
WE ARE NOW RECRUITING GRADUATE STUDENTS!
The Muller lab is interested in catalytic RNA molecules (ribozymes), with two specific questions:
1 - During the emergence of life, how could catalytic RNAs have mediated self-replication and evolution?
At early stages of life, before the existence of a ribosome (the protein translation machinery), catalytic RNAs (ribozymes) likely catalyzed most, if not all reactions necessary for self-replication and evolution. Support for this idea comes from the findings that the ribosome is a catalytic RNA, that most cofactors are derived from nucleotides, and that lab-generated RNAs are able to catalyze many different chemical reactions. To test how such an early stage of life could have functioned, we are generating novel catalytic RNAs with a technique called in vitro selection. We have identified ribozymes that can use the prebiotically plausible energy source 'cyclic trimetaphosphate' (cTmp) and generate GTP, one of the four nucleoside triphosphates (NTPs) that are required to polymerase RNA in every known life form. This cTmp can stands in equilibrium with diamido phosphate (DAP), which can also serve as energy source, and also phosphorylate nucleosides to generate NTPs. These two molecules (DAP and cTmp) may have acted as the central energy source of early life forms at different stages of evolution: DAP seems easier to generate prebiotically and is more reactive, therefore it may have been most important in the earliest stages. In contrast, cTmp may require more narrow conditions for its synthesis and is kinetically more stable, therefore it may have been ideal at a following stage of evolution. By generating, and characterizing ribozymes that use such energy sources we are working towards our long-term goal of generating, and studying an RNA-based model system for early life in the lab. Such a system would - in the lab - evolve into a more efficient replicator, and therefore guide our understanding of early, RNA-based stages of life. Additionally, evolving such a system in different chemical environments (for example, in the presence of amino acids) may show how such an early stage could have evolved into more sophisticated systems.
2 - Can catalytic RNAs be used to treat genetic diseases by repairing the mutations on the RNA level?
Natural group I intron ribozymes are cis-splicing, which means that they remove themselves from the primary transcript in two transesterification reactions. These cis-splicing ribozymes can be transformed into trans-splicing ribozymes. In that new format, the ribozyme can be used to repair genetic mutations on the RNA level. To be therapeutically useful the efficiency of these ribozymes needs to be increased. We are doing this by identifying the best splice sites on target RNAs, and by evolving the ribozymes for high activity in cells.
In related work we have re-engineered the ribozyme to splice on two splice sites. These spliceozymes recognize a target RNA at two splice sites, remove the intervening sequence, and join the two flanking sequences. Because this is analogous to the spliceosome we have termed these ribozymes 'spliceozymes'. We have evolved these ribozymes in bacterial cells for higher efficiency. The resulting ribozymes generate much more of the product sequence by a subtle re-balancing of the activities at the 5'-splice site and 3'-splice site. This re-balancing leads to a much lower formation of side products and consequently a more efficient conversion to the desired product.
Primary Research Area
Biochemistry
Interdisciplinary interests
Macromolecular Structure
Cellular Biochemistry
Bioorganic
Outreach Activities
CAMPUS EFFORTS
Advisory Service - Participant in developing the GE curriculum at Thurgood Marshall College in 2009. Thurgood Marshall College places an especially high importance on promoting diversity, for example in its specifically designed program Dimensions of Culture (DOC).
Recruitment Efforts - Assist in the recruitment efforts of the Thurgood-Marshall College, in two recruitment seasons.
Mentoring Efforts - Involvement in the Thurgood-Marshall mentorship program for transfer students, specifically aimed at helping disadvantaged transfer students.
COMMUNITY EFFORTS
My lab is dedicated to supporting an equal opportunity environment. This is reflected in the numbers of students in my lab: Three of the seven PhD students from my lab who have so far defended their thesis are female. Five of twelve undergraduate researchers who worked in my lab were female, and five of them were from an ethnic background (Asian/Hawaiian/African American).
From 2018 to 2020 I served as Vice Chair for Education, and from 2020 to 2022 I served as Vice Chair for Graduate Education in the Department of Chemistry & Biochemistry. Both roles served the needs of students on many different levels, including information sessions, meetings to solve specific problems, and a regular 'tea hour with VC Uli' to address any challenges faced by graduate students.
Selected Publications
- Lin H,Jiménez EI,Arriola JT,Müller UF,Krishnamurthy R "Concurrent Prebiotic Formation of Nucleoside-Amidophosphates and Nucleoside-Triphosphates Potentiates Transition from Abiotic to Biotic Polymerization.", Angew Chem Int Ed Engl, 2022, Vol. 61, Issue 1, e202113625
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- Müller UF,Elsila J,Trail D,DasGupta S,Giese CC,Walton CR,Cohen ZR,Stolar T,Krishnamurthy R,Lyons TW,Rogers KL,Williams LD "Frontiers in Prebiotic Chemistry and Early Earth Environments.", Orig Life Evol Biosph, 2022,
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- Trail D, Elsila J, Muller UF, Lyons T, Rogers KL "Rethinking the Search for the Origins of Life", Eos, 2022, Vol. 103,
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- Akoopie A,Arriola JT,Magde D,Müller UF "A GTP-synthesizing ribozyme selected by metabolic coupling to an RNA polymerase ribozyme.", Sci Adv, 2021, Vol. 7, Issue 41, eabj7487
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- Magde D,Akoopie A,Magde MD Jr,Müller UF "Water/Oil Emulsions with Controlled Droplet Sizes for In Vitro Selection Experiments.", ACS Omega, 2021, Vol. 6, Issue 33, 21773-21783
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- Arriola JT,Müller UF "A combinatorial method to isolate short ribozymes from complex ribozyme libraries.", Nucleic Acids Res, 2020, e116
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- Leier A,Bedwell DM,Chen AT,Dickson G,Keeling KM,Kesterson RA,Korf BR,Marquez Lago TT,Müller UF,Popplewell L,Zhou J,Wallis D "Mutation-Directed Therapeutics for Neurofibromatosis Type I.", Mol Ther Nucleic Acids, 2020, Vol. 20, 739-753
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- Pressman AD,Liu Z,Janzen E,Blanco C,Müller UF,Joyce GF,Pascal R,Chen IA "Mapping a Systematic Ribozyme Fitness Landscape Reveals a Frustrated Evolutionary Network for Self-Aminoacylating RNA.", J Am Chem Soc, 2019, Vol. 141, Issue 15, 6213-6223
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- Akoopie A,Müller UF "Cotranscriptional 3'-End Processing of T7 RNA Polymerase Transcripts by a Smaller HDV Ribozyme.", J Mol Evol, 2018, Vol. 86, Issue 7, 425-430
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- Akoopie A,Müller UF "The NTP binding site of the polymerase ribozyme.", Nucleic Acids Res, 2018, Vol. 46, Issue 20, 10589-10597
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- Müller UF "Design and Experimental Evolution of trans-Splicing Group I Intron Ribozymes.", Molecules, 2017, Vol. 22, Issue 1,
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- Pressman A,Moretti JE,Campbell GW,Müller UF,Chen IA "Analysis of in vitro evolution reveals the underlying distribution of catalytic activity among random sequences.", Nucleic Acids Res, 2017, Vol. 45, Issue 14, 8167-8179
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- Akoopie, A., Müller, U.F. "Lower temperature optimum of a smaller, fragmented triphosphorylation ribozyme", Physical Chemistry Chemical Physics, 2016, Vol. 18, 20118-20125
- Amini, Z.N., Müller, U.F. "Increased efficiency of evolved group I intron spliceozymes by decreased side product formation", RNA, 2015, Vol. 21, Issue 8, 1480-1489
- Dolan, G.F., Akoopie, A., Müller, U.F. "A faster triphosphorylation ribozyme", PLoS ONE, 2015, Vol. 10, Issue 11, e0142559
- Martin, L.L., Unrau, P.J., Müller, U.F. "RNA synthesis by in vitro selected ribozymes for recreating an RNA world", Life (Basel), 2015, Vol. 5, Issue 1, 247-268
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- Amini ZN, Olson KE, Müller UF, "Spliceozymes: Ribozymes that Remove Introns from Pre-mRNAs in Trans.", PLoS One, 2014, Vol. 9, Issue 7, e101932
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- Dolan G.F., Müller U.F. "Trans-splicing with the group I intron ribozyme from Azoarcus", RNA, 2014, Vol. 20, Issue 2, 202-213
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- Moretti J.E., Müller U.F., "A ribozyme that triphosphorylates RNA 5'-hydroxyl groups.", Nucleic Acids Res., 2014, Vol. 42, Issue 7, 4767-4778
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- Müller UF, Tor Y, "Citric acid and the RNA world.", Angew Chem Int Ed Engl, 2014, Vol. 53, Issue 21, 5245-7
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- Olson KE, Dolan GF, Müller UF, "In vivo evolution of a catalytic RNA couples trans-splicing to translation.", PLoS One, 2014, Vol. 9, Issue 1, e86473
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- Amini ZN, Müller UF, "Low selection pressure aids the evolution of cooperative ribozyme mutations in cells.", J Biol Chem, 2013, Vol. 288, Issue 46, 33096-106
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- Meluzzi D, Olson KE, Dolan GF, Arya G, Müller UF, "Computational prediction of efficient splice sites for trans-splicing ribozymes.", RNA, 2012, Vol. 18, Issue 3, 590-602
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- Olson KE, Müller UF, "An in vivo selection method to optimize trans-splicing ribozymes.", RNA, 2012, Vol. 18, Issue 3, 581-9
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- Yao C, Moretti JE, Struss PE, Spall JA, Müller UF, "Arginine cofactors on the polymerase ribozyme.", PLoS One, 2011, Vol. 6, Issue 9, e25030
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- Yao C, Müller UF, "Polymerase ribozyme efficiency increased by G/T-rich DNA oligonucleotides.", RNA, 2011, Vol. 17, Issue 7, 1274-81
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- Müller UF, "Evolution of ribozymes in an RNA world.", Chem Biol, 2009, Vol. 16, Issue 8, 797-8
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- Müller UF, Bartel DP, "Improved polymerase ribozyme efficiency on hydrophobic assemblies.", RNA, 2008, Vol. 14, Issue 3, 552-62
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- Müller UF, "Re-creating an RNA world.", Cell Mol Life Sci, 2006, Vol. 63, Issue 11, 1278-93
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- Müller UF, Bartel DP, "Substrate 2'-hydroxyl groups required for ribozyme-catalyzed polymerization.", Chem Biol, 2003, Vol. 10, Issue 9, 799-806
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- Müller UF, Göringer HU, "Mechanism of the gBP21-mediated RNA/RNA annealing reaction: matchmaking and charge reduction.", Nucleic Acids Res, 2002, Vol. 30, Issue 2, 447-55
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- Müller UF, Lambert L, Göringer HU, "Annealing of RNA editing substrates facilitated by guide RNA-binding protein gBP21.", EMBO J, 2001, Vol. 20, Issue 6, 1394-404
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