Richard Roberts Associate Professor Chemistry, Chemical Engineering College of Letters Arts & Sciences Viterbi School of Engineering

Education:
BS 1987 Chemistry - University of Kansas, Lawrence, Kansas
PhD 1993 Biophysical Chemistry - Yale University, New Haven, CT

Postdoctoral Research Fellowship:
1993 - 1997 Harvard Medical School and Massachusetts General Hospital

Started at USC: 2005

Research Topics: Protein Chemistry/Enzymology, DNA & RNA, Signal Transduction, Aging, Structural Biology

Research Description

My research focuses on the protein synthesis machinery both as a tool for polypeptide design and as a target that can be probed using chemical means. A key aspect of my lab’s work is peptide and protein design using in vitro selection experiments. Toward this end, we use mRNA display, a technique I conceived and implemented to enable polypeptide design (1) (see figure below). This approach allows my lab to create and sieve more than 10 trillion independent peptide or protein sequences for function, the most of any technique currently available (reviewed in (2)). In applying any design approach, it is optimal if key issues, including affinity, specificity, diversity, structure, dynamics, and biological activity can be addressed in a principled way. My desire has been to build and execute a research program that tackles all of these issues.

My passion is using the tools of chemistry to understand and control biological processes. We have applied our design approach to address biological control, molecular recognition, stability, and dynamics in RNA-peptide complexes (3-10), G proteins (11-13) and G protein coupled receptors (GPCRs) (14). In the future, our efforts should provide new tools for systems biology and leads for therapeutic development.

mRNA display. An mRNA template (black line) covalently attached to puromycin is used to program an in vitro translation reaction. After protein synthesis, the puromycin enters the ribosome in cis to form a covalent mRNA-protein fusion.

We are also very interested to re-engineer the protein synthesis machinery to create unnatural mRNA display libraries. This project, a nanoscale engineering effort, works to merge the power of display selections with the flexibility of combinatorial chemistry. To do this, my lab has worked to extend mRNA display beyond the natural genetic code, in an effort to create new and richly diverse compositions of matter for ligand design, drug discovery, and beyond (15-18) (reviewed in (19)).

In conjunction with our re-engineering efforts, we have become intensely interested in thinking about the ribosome as a target. Our work began with efforts to understand the ribosome's substrate specificity (20-22). These efforts have also yielded unexpected and exciting new reagents that have enabled us to visualize protein synthesis in vivo in T-cells (23) and neurons (24) with spatial and temporal resolution.

Finally, my intellectual interest in evolution and the origin of life has lead me to work on a model for the origin of the ribosome (25) and a proposal for how Darwinian evolution could have begun via coupling genome replication and cellular growth (26).

Overall, my research bridges Chemistry, Biology, and Engineering with the goal of bringing new approaches to molecular design, systems biology, and therapeutics. I have pursued these goals in both formal and informal collaborations at Caltech (J. Alberola-Ila, S. Benzer, P. Bjorkman, D. Dougherty, B. Hay, E. Schuman, A. Varshavsky, A. H. Zewail) and at other universities (S. R. Sprang UTSW, N. Strynadka UBC, J. W. Szostak Harvard Med., L. Jan UCSF).