I study RNA structure-function and its recognition by proteins and small molecules. There is a dual theme our research. On the one hand, I seek to understand fundamental biophysical and biochemical aspects of RNA and RNA-protein complexes. On the other, I build from this knowledge to design, synthesize and assay new molecules that interfere with the function of RNA and its complexes. Our dual interest has been reflected in our Academic achievements, but also in a successful start-up, Ribotargets, that I co-founded in 1996, one of the first companies which sought to exploit RNA as a drug target. In the future, I will continue to seek a better fundamental understanding of post-transcriptional regulation of gene expression, and to exploit this knowledge to discover new molecular entities to treat human disease by interfering with the function of RNA.

Understanding RNA structure and RNA-protein recognition is central to biology

It is ever increasingly appreciated that many steps in the regulation of gene expression, especially in higher organisms, occur after transcription and that RNA is the central player. These processes are fundamental aspects of biology and allow for multiple levels of regulation in response to extracellular or genetic signals. The discovery in the last 10 years of microRNAs and many non-protein coding transcripts has revolutionized our understanding of biology, for example of epigenetic mechanisms of transcriptional regulation which often rely on RNA-mediated targeting of specific genomic loci. The aim of the group is to understand how RNA folds and proteins bind to RNA well enough that we can not only understand the biophysical and biochemical basis of recognition and regulation, but to rationally design new proteins, peptides and ultimately small molecule drugs that control human regulatory networks or repress viral replication.

RNA-protein interactions and human disease

Since >70% of all genetic variation in humans occur within regulatory regions, understanding RNA metabolism is also essential to analyze the genetic basis of the differential response to medical treatment or susceptibility to disease. Furthermore, anomalous expression or misregulation of RNA coding genes is causally associated with human disease and therefore provide inviting targets for intervention. These opportunities, though, cannot be fully exploited unless we expand the chemistry of RNA binding molecules beyond oligonucleotide analogues.

Multiple experimental and computational approaches are used to achieve these goals

NMR spectroscopy remains the central tool of my group because it is very well suited to study RNA structures that are sometimes not as amenable to crystallography as more tightly folded globular proteins. New isotopic labeling techniques and advances in instrumentation expand the size of molecules amenable to NMR, but this technique retains limitations at large molecular weight. Thus, we supplement solution NMR with solid state NMR, x-ray crystallography, EM as well as lower resolution techniques such as SAXS and chemical probing, and use computational tools, to determine RNA structures and guide the synthesis of molecules that bind to RNA.