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). We address two very different questions: (1) How did the RNA world, an early stage of life, function? To do this we develop catalytic RNAs by in vitro selection from random RNA sequences. Our long-term aim is to generate an RNA world organism and thereby recapitulate an early stage of life in the lab. (2) How can experimental evolution improve trans-splicing ribozymes? This question is important because such experimental evolution could recapitulate biochemical steps in the evolution of the spliceosome, and because evolved trans-splicing ribozymes may be useful for therapeutic applications.

Ribozymes and the origin of life

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. 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/RNA/protein life forms. The focus of our work is on ribozymes that generate chemically activated nucleotides, and polymerize chemically activated nucleotides. Both activities are essential for the self-replication of an RNA world organism. Using in vitro selection from more than 10^14 sequences, we identified ribozymes that are able to catalyze the triphosphorylation of RNA 5'-hydroxyl groups using trimetaphosphate. Because trimetaphosphate likely existed on early Earth, our findings show that trimetaphosphate could have been used 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 integrate them into a larger system of self-replicating ribozymes, an RNA world organism.



Evolution of trans-splicing ribozymes in cells

Group I intron ribozymes are among the most well-studied and versatile ribozymes. In contrast to the natural, cis-splicing versions of group I intron ribozymes we are using engineered, trans-splicing group I introns. These ribozymes can specifically recognize target sites on mRNAs by base pairing and remove or replace sequences in the target mRNA. We engineered ribozyme variants that splice efficiently on two splice sites, and termed them 'spliceozymes'. Analogous to the spliceosome, these spliceozymes remove an internal sequence from a target RNA and join the flanking sequences, resulting in a translatable mRNA. Because self-splicing group II introns share a common ribozyme ancestor with the spliceosome we are now using the 'group I intron spliceozymes' as model system for biochemical steps in the evolution of the spliceosome. To do that we developed an evolution scheme that repeatedly generates about 1 million ribozyme variants and selects them for efficient splicing in cells. After about a dozen cycles, this evolution system generated spliceozyme variants that used several mechanisms to increase product formation and decrease side product formation. Future evolution and optimization may show how specific biochemical steps could have been taken in the evolution of the spliceosome, and may make these ribozymes useful as tools in therapy.
Primary Research Area
Biochemistry
Interdisciplinary interests
Macromolecular Structure
Cellular Biochemistry
Bioorganic

Outreach Activities
CAMPUS EFFORTS

Advisory Service - Active 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


Members of the Muller lab: Logan Norrell, Uli Muller, Angel Guan, Greg Dolan, Zhaleh Amini, Arvin Akoopie, Sarah Wagstaff.

Triphosphorylation of RNA 5'-hydroxyl groups by trimetaphosphate.


Uli Muller pipetting
Selected Publications