High Priests of RNA Assemble: Five Days of Science & Magic in Krakow
Last month I had the opportunity to attend the RNA Society Meeting in Krakow to present a poster on iMaps, the data repository and analysis tool for RNA-protein binding—as measured by CLIP-seq— Genialis has been working on this past year.
After months of managing people and projects, I was looking forward to immersing myself in science once again. The phenomenal lineup of speakers featured keynote lectures by the likes of Phillip Sharp, Nobel Laureate, entrepreneur & grandpa extraordinaire. I was also excited to highlight some of Genialis’ tangible contributions to the field after years of hard work. The future of RNA in biomedicine looks promising, and I’m proud to help forge the path ahead!
Set in the palatial backdrop of the Wawel Castle, the talks at the conference covered everything from novel sequencing technologies to RNA vaccines with surprising twists on conventional topics (think ribosomes). I wish I could cover it all, but for now I’ve highlighted topics I found most interesting below. Technical details aside, what I hope to convey most is the magic of biology and the science of what’s possible. While I’m still digesting the avalanche of information, a game-changing realisation that has slowly crept into our collective consciousness rings loudest: RNA always operates in tandem with proteins, and this interplay presents exciting new opportunities (and challenges!) for precision therapeutics.
The first day started out with a keynote lecture from the venerable Dr. Phillip Sharp. His talk, entitled “RNA Biology in Gene Regulation”, discussed “molecular condensates”. He contends membrane-less bodies in cells have the properties of liquids and are likely formed through phase transitions mediated by weak multivalent interactions. It turns out super enhancers are also transient, membrane-less condensates. In this way, transcription further controls translation, opening up an entirely new dimension for pharmacological intervention. Learn how – and you get a billion-dollar drug as a reward. Learn why – and you get a glimpse of God.
Dr. Sharp does not for a moment believe the rapid fusions and fissions of these condensates is an arbitrary event guided by brownian motion, oh no, these must be regulated by agents yet unknown. Feel the excitement yet?
The day ended with a moving piano concert, giving me a chance to cool off and take it all in. Chopin’s Mazurkas embody life and its ups and downs in full color and all three dimensions. I wonder if they’d let me put a piano in the break room…
The second day was a lot of “molecular” and very little “biology”. Structural biology has its merits, of course, but one can only digest so many 3D structures in a day. Nonetheless, I soldiered on and learned DNA binding proteins bind RNA, often very promiscuously and with even greater affinity than DNA. This unsurprisingly has profound effects on regulation and phenotype. Further, virtually all non-coding RNA operates with RNA-binding proteins (RNP complexes). Some went so far as to suggest the RNA Society should be renamed to RNP Society. Blasphemy, obviously. (I overheard some of the youngsters discussing this idea once the old guys went to bed).
Another particularly fascinating area of research is “arm switching” in micro RNAs – a phenomenon in which either part of an RNA hairpin is used to interact with other moieties. Uridylation and adenylation appear to play a major role, so it is likely a tightly regulated process that may play a crucial role in disease.
Towards the end of the day, I had a chance to take a solo hike along the Vistula river and cool down under the arches of Saints Peter and Paul Church in downtown Krakow. Finding myself surrounded by statues of the pope, impossible large churches and the grandeur of Wawel Royal Castle, it’s hard not to get carried away. I ended the day with quiet contemplation, marveling at a great mystery of RNA, life and god(s).
The third day was all about RNA therapeutics. There aren’t many of them out there—exactly 2 drugs, exondys and spinraza, have been approved so far. That said, there are several in clinical development. Everyone is understandably excited, seeing as how the market for spinraza alone is a mind boggling $1.7 billion. Of course, game changing drugs come with their fair share of controversy. One year of spinraza treatment costs $750k per person, followed by a $300k yearly discount, if you survive…
Drug pricing has been at the center of heated debates both in the EU and North America, but the ethics and market compulsions are well beyond the scope of this blog (and can get cynical to the point of depression if left to discuss unattended). For what it’s worth, its predicted the cost of RNA therapeutics will decrease significantly in the coming years. Interestingly, manufacturing of a yearly dose of spinraza only costs about $100 per person. Perhaps the most shocking realization over the last couple of years appears to be the sheer simplicity of delivering RNA based drugs. Intramuscular or intraspinal injections of naked RNA almost magically finds its way to the target tissue/cell and last for up to a year. RNA vaccinations may replace the daily pill in some diseases and may well become the drugs of the future.
I’d like to take a moment to talk about illegal spinraza. Physicians across the EU and North America have observed side effects of spinraza in patients who shouldn’t have had access to the drug. That’s right, if the world wasn’t crazy enough for you, there’s now a black market dedicated to making people healthy! If that doesn’t sound like the plot of an action movie starring Steven Seagal, rogue pharmacologist, I don’t know what does.
The fourth day focused on all things ribosome. Ribosomes constitute a third of dry mass of a mammalian cell, which means a mind boggling average of 10 million ribosomes per cell!
While we’ve known proteins impact the fate of RNA (e.g. mark it for degradation), we are now discovering riboregulation – a process where a protein fate is determined by linked RNA. Ribosomes were largely thought of as pretty much identical, but recent work has demonstrated they contain up to 200 additional assembly factors comprising structural proteins, enzymes, and RNA. What I found most fascinating was different types of ribosomes have been shown to exclusively process certain networks of RNA, in a manner analogous to bacterial operons. This wonderful talk was delivered by Maria Barna (Stanford), an Early Career Award winner. I certainly look forward to listening to her again this fall when she attends a gig in my neighborhood. (http://meetings.embo.org/event/19-rnp-networks)
Our poster on iMaps was one of roughly 300 posters presented that evening. Even so, it generated a lot of interest and I found myself with dry mouth and out of breath after talking for nearly 3 hours non-stop. It’s exhilarating, albeit exhausting, when your work creates so much interest. Still, a welcome change from my days as a lowly graduate student.
For the uninitiated, iMaps is a tool Genialis developed in collaboration with the Ule lab (UCL Institute of Neurology, London, UK) to standardize CLIP data management & analysis. iMaps endeavors to be the world’s largest continuously curated database of CLIP data, and already hosts hundreds of annotated samples available to the public. You can check out our poster here or check out our iMaps server here.
The morning session, entitled “Interconnected RNA”, attempted to show how all RNA-related processes are interconnected. RNA transcription directly influences translation and degradation, even though transcription takes place in the nucleus and translation/degradation happens in the cytoplasm. The entire process is mediated by a host of RNA binding proteins, which I’m sure you’ve figured out was the crux of the conference. We now know the immune system, for example, is regulated in intricate ways at the RNA level. We are but glimpsing mechanisms that may come to change medicine as we know it.
I had a chance to attend a session on computational methods for RNA analysis before my flight back home. There were interesting presentations about methods for RNA splicing analysis, Grad-seq (RNA-Seq + MassSpec), measuring lengths of Poly(A) tails using Oxford Nanopore sequencing, and ClickSeq (another kind of 3’-end sequencing). I had a chance to present iMaps once again, with Jernej Ule and Gene Yeo (Eclipse Bio, CA) beaming from the front rows. A little bit of competition always helps make the game of science a little more…interesting 😉
The RNA Society Meeting left me with a profound sense of wonder and appreciation for all the hard work of my peers, and the giants on whose shoulders we stand. I feel reinvigorated and energized to continue my work at Genialis, and I hope to update you on our progress in the coming months.
About the Author
Luka Ausec, PhD
VP Scientific Discovery
Luka directs internal R&D and partnership projects, and manages the customer-facing team of informatics support specialists. He ensures Genialis delivers model driven insights that exceed partner expectations. A microbiologist turned bioinformatician, Luka enjoys teaching Python and tai chi in his free time.
Genialis is a data science company based in San Ramon, California, Houston, Texas, and Ljubljana, Slovenia. Genialis’ team of biologists and data scientists is passionate about helping realize the promise of precision medicine. Recognizing that each patient’s biology is their own, Genialis champions an approach to developing model that consider diverse data in concert with focused experiments and trials.
For more information, visit www.genialis.com and follow @genialis on LinkedIn and Twitter. Or contact:
CCO, Genialis, Inc.