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

Contact Information
Professor of Chemistry and Biochemistry

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
2022 - present Professor, UC San Diego
2014-2022 Associate Professor, UC San Diego
2006-2014 Assistant Professor, UC San Diego
2001-2006 Postdoctoral Researcher, Whitehead Institute, Cambridge, MA
Awards and Academic Honors
2022-25
NASA research award
2021-26
NASA research award
2020-22
Cystic Fibrosis Foundation
2019-22
NASA research award
2018-20
Gilbert Gene Therapy Initiative
2016-19
NASA research award
2013-16
NASA research award
2011-13
Hellman Fellow
2008-11
NSF research award
2004-05
NRSA fellowship from the NIH
2001-04
Postdoctoral award from the German Research Council (DFG)
Research Interests
WE ARE NOW RECRUITING GRADUATE STUDENTS!

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. cTmp may have acted as the central energy source of early life forms. This selection was the first selection to directly select a trans-acting ribozyme in emulsion droplets - in fact 10^16 droplets.

In addition, we are selecting ribozymes in different environmental conditions to test what kind of conditions would have been most promising for an RNA world system to arise. For example, we found that ribozymes can not only use the abundant Mg2+ ions but also the less abundant but catalytiucally more potent lanthanide3+ ions. For example we selected ribozymes in the presence of short, prebiotically plausible peptides and found that the peptides alone may not have had a strong benefit for the ribozymes, but peptides coupled to (prebiotically plausible polyarmatic hydrocarbons such as naphtalene and flourene can strongly enhace ribozyme catalysis. By successively building a system of ribozymes that could form a self-replicating system, and by doing that in different chemical environments, we hope to unravel in the future how our distant ancestors - RNA world organisms - could have looked like and functioned.



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. We have re-engineered, and re-evolved the ribozyme to in vitro, and in bacterial cells for increased efficiency and specificity. The long-term goal is to develop a therapeutic ribozyme for mRNA editing, either to repair genetic mutations or to specifically kill cells that indicate a disease status.
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 from 2020 to 2022 I served as Vice Chair for Graduate Education in the Department of Chemistry & Biochemistry. Both roles served the needs of students on many different levels, 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