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

Contact Information
Associate Professor
Vice Chair for Graduate Education

Office: Urey Hall 5218
Phone: 858-534-6823
Group: View group members
2000 Ph.D., University of Technology Darmstadt, Germany
1995 BS, LMU Munich, Germany
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
Cystic Fibrosis Foundation
NASA research award
Gilbert Gene Therapy Initiative
NASA research award
NASA research award
Hellman Fellow
Hellman Fellow
NSF research award
NRSA fellowship from the NIH
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 early evolution of life, how could an 'RNA world' have emerged, how could it have looked like, and how could it have functioned?

The earliest evolutionary stages of life included a stage without encoded protein synthesis, and likely with RNA serving both as genome and as the only genome-encoded catalyst. This idea is called the RNA world hypothesis. Support for this idea comes from the findings that the ribosome (the protein translation machinery) is a catalytic RNA, that most cofactors are derived from nucleotides, and that RNAs are able to catalyze many different chemical reactions. We are using in vitro selections to generate specific catalytic RNAs that could have been important in an RNA world. By characterizing their frequency in sequence space, their activity, and their dependence on cofactors, we are trying to find out how an RNA world (or a similar scenario) could have emerged from a prebiotic environment, under which conditions this would have been most likely. Our long-term goal is to generate an RNA world organism in the lab. Because such a system would by definition evolve into a more efficient replicator it would teach us about self-replicating, and evolving molecular systems, and what different evolutionary pathways and outcomes would have been possible in different chemical environments.

The focus of our work is currently on ribozymes that use the prebiotically plausible molecule trimetaphosphate (Tmp) as energy source. This molecule could have supplied the energy that is essential for the self-replication of an RNA world organism. Using in vitro selections from more than 10^14 sequences, we identified ribozymes that are able to catalyze the triphosphorylation of RNA 5'-hydroxyl groups using trimetaphosphate. These findings showed that ribozymes would have been able to use trimetaphosphate as energy source for RNA world organisms. Current research in our lab aims to generate variants of these ribozymes that could fuel a primitive energy metabolism, and ultimately generate an RNA world organism in the lab. This would be exciting because it would allow us to completely understand a life-like system based on all mutual molecular interactions, and it would allow us to follow their evolution over time, and understanding the origin of our distant ancestors.

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
Interdisciplinary interests
Macromolecular Structure
Cellular Biochemistry

Outreach Activities

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.


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

The Muller lab. From left to right: Xu Han, Debolina Sarkar, Josh Arriola, Jehanne Aghzadi, Kevin Sweeney, Uli Müller.

Selected Publications