Personal reflection (RNA journal 20th anniversary).

I count myself among the fortunate. I get to do science for a living. I spend my days pouring over data, trying to understand what they mean, and testing ideas both reasonable and half-baked. I interact with amazing people every day. They come to my University from the far reaches of the planet. I write. I think. I brainstorm with students and colleagues. On the best days, I perform an experiment. More than anything, I enjoy creative problem solving—trying to find unique solutions to complicated problems with multiple unknown variables. This is my passion. This is my career. I began my research path approximately one year after the first issue of the RNA journal was published. I started as graduate student in Molecular Biophysics and Biochemistry at Yale University in the Fall of 1996. I chose to go to Yale for a variety of reasons, but in essence it boils down to my fascination with RNA as a biological catalyst. I interviewed at Yale shortly after the structure of the P4-P6 domain of the Group I intron was solved by Doudna, Cech, and colleagues. The excitement in the department was palpable. This was the largest RNA structure to be determined since tRNAwas published in the early 1970s by the Rich lab. It was immediately clear from the work that RNA could adopt complicated shapes; that two RNA helices could pack together tightly; and that much more work was necessary to understand how structure led to function. For this reason, I chose to pursue graduate studies in Scott Strobel’s lab. He had developed an approach called Nucleotide Analog Interference Mapping that enabled chemical group resolution insights into an RNA’s activity. The approach, while relatively simple, was an extraordinarily useful tool to probe RNA structure-function questions. The challenge was interpretation in the absence of a structure, as the approach could not easily distinguish among groups involved in structure formation, ligand binding, and chemical mechanism. Luckily, I worked on the hairpin ribozyme, and my good friend and colleague Adrian Ferré-D’Amaré—whom I met when he was a post-doc in Jennifer Doudna’s lab— solved the high-resolution crystal structure of this ribozyme shortly after setting up his own lab. His structure provided the platform I needed to interpret the data that I collected, ultimately enabling the completion of my PhD research and publication of my final research paper as a graduate student (in RNA). Thanks Adrian. I am sure that I still owe you beverage in payment for the timeliness of your discovery. The RNA structure field exploded while I was a graduate student (1996–2001), with crystal structures of the hairpin, hammerhead, and hepatitis delta virus ribozymes, and, of course, the myriad structures of the ribosome in various states from a variety of labs around the world. It was an impressive expansion in our knowledge of RNA structure. This work spawned intensive studies into chemical mechanism of RNA catalysis that continue to this day. Metal ion-mediated mechanisms that had long been postulated were revealed in three dimensions. We learned that RNA could act as an acid-base catalyst. New ideas about the chemical mechanism of the ribosome were formulated and put to the test. It was an exciting time to be a student. Watching the pace of new discoveries was lesson in the value of an open collaborative environment. Not just among the faculty, but within the student and post-doc population as well. Coffee breaks turned into discussions about methods, tips and tricks, pitfalls to avoid. Lunchtime was practically an informal group meeting. What are you up to today? How’d your experiment turn out yesterday? Happy Hour on Friday was a celebration of the week’s accomplishments (or failures, which in truth are really accomplishments if you keep an open mind). I benefited from numerous smart people thinking about my projects, and I did my best to provide insights to their work in kind. It was fun. We had an expectation of success and an eye towards the future. Many of my colleagues did go on to run successful independent research labs. I follow their work to this day. Now it’s 2015 and much has changed. I’m older, balder, and a little less wild than I was as a graduate student. I’ve come to appreciate the value of scientific discovery not just as a learner, but as a patient too. (Thank you Professor Vilcek and colleagues for Remicade.) As I monitor the literature, I see incredible discoveries continue to be published at an astonishing rate. Most notably, the field of non-coding RNA biology has rapidly advanced in the past 20 years. From the initial discovery of miRNAs, to RNAi technology, piRNAs,