As MicroRNAs Make First Clinical Impact, Janssen Prize 2012 Awarded for Their Discovery

20 years ago, Gary Ruvkun and Victor Ambros made the startling discovery that a tiny noncoding RNA, lin-4, could be a key regulator of C. elegans development by downregulating messenger RNAs through Watson-Crick base-pairing.  What for a number of years seemed like an oddity of worm biology has become the first example for a whole new fundamental class of biological molecules, rivaling in importance messenger RNAs: essentially every biological pathway is regulated by a microRNA.     

Not only have microRNAs fundamentally re-shaped our thinking about molecular biology, they have also made quick inroads into the clinic.  Even before RNAi Therapeutics, microRNA-based diagnostics are already making a clinical impact today.  Half a dozen such tests have been commercially launched.  The currently arguably medically most impactful among them, mirViewMets(2) for the diagnosis of Cancers of Unknown Primary by Rosetta Genomics received Medicare coverage in May of this year.  This in the diagnostics is tantamount to the regulatory approval of a drug candidate in the therapeutics space.

On the microRNA therapeutics front, the miR-122 inhibitor by Santaris for the treatment of HCV infection is the most advanced.  Studies with this antisense inhibitor have yielded intriguingclinical data, including the suppression of viral loads to undetectable levels. A number of other miRNA drug candidates are in late preclinical development.

Considering the general biological importance of microRNAs and their rapid translation into the clinic, it is not all that surprising that Gary Ruvkun and Victor Ambros were recognized with the 2012 Dr. Paul Janssen Award for Biomedical Research.  This prize is one of the premier accolades in biomedical research for inspirational scientists that have undertaken ground-breaking science with great medical impact.  Surely, the discovery of microRNAs and their discoverers fit that bill.  Without lessening the importance of the prize and the contributions of corporate sponsor J&J, many of these prizewinners will go on to win the Nobel Prize.  I fully expect Ambros and Ruvkun to do so, too.

Daring Resesarch on the Cutting Edge

One cannot overestimate the scientific accomplishment of the work by Ambros and Ruvkun.  At the time, the notion of small RNAs as genetic regulators was simply unheard of.  It was thus the accomplishment of the Ambros group to embrace the possibility that their odd genetic mapping results during a worm developmental timing project pointed towards such a class of molecules. 

The lab-books around the world are littered with curious findings that never get followed up on because we think that they are likely caused by some experimental artifact and we would no get anything else done if we chased after each of them.  And even when the evidence is so clear before your eyes (e.g. that band in the low molecular weight range), the conditioned eye will simply ignore it.  In this case, the initial disbelief was only overcome by sequencing and re-sequencing before Ambros and colleagues had to finally accept that the mutation was indeed in a region without a proper open-reading frame (= protein).  Moreover, the recognition that a small RNA was the molecule affected by the mutation required that RNAs of all sizes were considered despite the fact that at the time small RNAs were not meant to be captured by the laboratory gels.  And when they accidentally were, such small RNAs surely were artefactual junk.

Discovering microRNAs as a whole new class of key genetic regulators was just one accomplishment.  Another one was deciphering their mechanism of action.  As long-time fellow researchers of worm development, Ruvkun and Ambros were familiar with the genetic interactions of the lin-4 mutant.  One gene in particular, protein-coding gene lin-14 appeared to be suppressed by lin-4.  A deletion mutant in the 3’ UTR of lin-14 found by the Ruvkun group abolished this genetic interaction.  Noticing that there was sequence complementarity between lin-4 and the missing lin-14 3' UTR fragment, it dawned upon the two scientists almost in unison that lin-4 must be interacting with lin-14 through Watson-Crick base-pairing, thereby silencing it post-transcriptionally.

Award Symposium in New York

If you want to learn more about the discovery of microRNAs, their biology and medical importance, and also meet the scientists, you can register for the Dr. Paul Janssen Award Symposium to be held on September 7, 2012 at the New York Academy of Sciences.  It will be a great opportunity for both academic scientists and the biotech crowd to leave the lab bench and trading desks behind them for a few hours and reflect on the importance of basic research, in model organisms as seemingly obscure as the worm, for advancing medicine.

The RNAi Therapeutics Blog is a proud promotional partner of the Symposium.