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). Our main efforts are focused on the question: 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.

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.

A second line of projects in the lab is focused on Group I intron ribozymes, and their evolution in cells. Natural group I intron ribozymes are cis-splicing; we work with engineered, trans-splicing variants. 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. We use these 'group I intron spliceozymes' for two purposes: First, the evolution of these spliceozymes may enable us to recapitulate biochemical steps in the evolution of the spliceosome. Second, evolved variants of the spliceosomes may be useful for the therapy of diseases in which specific introns are incompletely removed.
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 Arreola, Kevin Sweeney, Ishani Behera, Arvin Akoopie.
Selected Publications