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
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 early evolution of life, how did the 'RNA world' stage look, and function?

The earliest evolutionary stages of life most likely included a stage called the RNA world. In this scenario, RNA served both as genome and as the only genome-encoded catalyst. These functions were later mostly overtaken by DNA and by proteins. By generating specific catalytic RNAs that could have been important in an RNA world, and by characterizing their frequency in sequence space, their activity, and their dependence on cofactors, we are trying to lay out the conditions that would most likely have allowed an RNA world system to emerge from a prebiotic environment.

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
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).
Image Gallery


The Muller lab. From left to right: Uli Muller, Logan Norrell, Joshua Arriola, Kevin Sweeney, Ishani Behera, Arvin Akoopie.

Selected Publications