Splicing: still so much to learn

This issue marks the 20th year since the launching of RNA in March of 1995. It is a time to celebrate, as well as to consider the substantial accomplishments achieved in these two decades, both in the RNA field as a whole, and in the specific areas in which each of us works—in my case, human pre-mRNA splicing mechanisms and regulation, and its relevance to human disease. Moreover, this is a time to reflect about where our field is headed, and what are the unique opportunities and obstacles in our path. With no intention of being exhaustive in listing major achievements, I would first single out certain technical advances from which virtually everyone in the RNA field and beyond is substantially benefitting, and which satisfyingly emerged from careful characterization of novel natural phenomena. One of these is RNA interference, which has led to various powerful, widely used tools for targeted gene knockdown, as well as to major efforts in therapeutics development. A more recent example consists of the prokaryotic CRISPR/Cas systems, which are rapidly being adapted as powerful tools for targeted genome editing. Other important technical developments include methods for massively parallel RNA-sequence analysis, and related techniques for systematically footprinting binding sites of proteins or RNP complexes on RNA (e.g., ribosome profiling, CLIP). These methods take advantage of the availability of complete or nearly complete genome sequences, and require appropriate use of computational and statistical tools