Muller, Ulrich
Evolution of catalytic RNAs, and the Origin of Life

Contact Information
Associate Professor

Office: Urey Hall 5218
Phone: 858-534-6823
Email: ufmuller@ucsd.edu
Web: www.ucsd.edu
Group: View group members
Education
2000 Ph.D., University of Technology Darmstadt, Germany
1995 BS, LMU Munich, Germany
Appointments
2014-present Associate Professor, UC San Diego
2006-2014 Assistant Professor, UC San Diego
2001-2006 Postdoctoral Researcher, Whitehead Institute, Cambridge, MA
Awards and Academic Honors
2021-2026
NASA research award
2020-2022
Cystic Fibrosis Foundation
2019-2022
NASA research award
2018-2020
Gilbert Gene Therapy Initiative
2016-2019
NASA research award
2013-2016
NASA research award
2012-2013
Hellman Fellow
2011-2012
Hellman Fellow
2008-2011
NSF research award
2004-2005
NRSA fellowship from the NIH
2001-2004
Postdoctoral award from the German Research Council (DFG)
Research Interests
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 since 2020 I am serving as Vice Chair for Graduate Education in the Department of Chemistry & Biochemistry. Both roles served the needs of students on many different levels. In my current role as VCGE I am addressing the needs of departmental graduate students in many different forms, including information sessions, meetings to solve specific problems, and a regular 'tea hour with VC Uli' to address any challenges faced by graduate students.
Image Gallery


In emulsio selection for a GTP synthase ribozyme. (A) Schematic of the selection system (B) DLS analysis of the emulsion (C) Kinetic Analysis of GTP synthesis..

Coupling of GTP synthesis with RNA polymerization in a minimal metabolic system,


The Muller lab. From left to right: Xu Han, Debolina Sarkar, Tommy Le, Josh Arriola, Uli Müller

Selected Publications