When Good Experiments Go Wrong…

Many of the revolutionary discoveries in science are driven by experiments gone wrong.  Typically, it is not because of bad experimental design or other common causes of artifacts.  It is because a previously unknown core scientific principle is revealing itself in ways we are unable to comprehend.  Sometimes the genius that is recognized in the award of a Nobel Prize is the ability of an investigator(s) to apply sound scientific principles in the appropriate way (and ignore dogma) to explain the phenomenon.

Serendipity strikes again!  The Nobel Prize in Physiology or Medicine for 2006 was awarded to Andrew Fire and Craig Mello for their breakthrough discovery of RNA interference (RNAi)[1].  RNAi denotes a set of post transcriptional gene regulatory phenomena mediated by small non-coding RNA molecules that appear to play a fundamental role in biology.  Fire and Mello were the first to elucidate the core mechanism underlying this essential cellular apparatus for controlling the flow of genetic information.

Photo: L. Cicero/Stanford Andrew Z. Fire

Photo: R. Carlin/UMMAS Craig C. Mello

To fully appreciate the implications of their work, we can review the “Dogma of Molecular Biology”, which describes the genetic blueprint of an organism.  The blueprint is encoded in the double stranded DNA structures from which the instruction manual is produced as one RNA strand per gene (i.e., the messenger RNA, mRNA also known as the “sense” strand).  The mRNA serves to direct the assembly of the corresponding protein.  Proteins are the biomolecules responsible for many functional and structural properties of an organism.  Critical to our ability to understand the intricacies of this central dogma is an understanding of how the expression and transfer of information is regulated. Therefore, by uncovering a novel regulatory process, Fire and Mello laid the foundation for a new discipline that enhances the field of Biotechnology the goal of which is to modify or improve basic biological processes in agriculture (e.g., enhance coloration or improve stress resistance) and medicine (e.g., develop diagnostic and therapeutic approaches for cancer). 

The RNAi phenomenon was actually first observed many years before Fire and Mello’s seminal publication and it was the result of good experiments gone wrong.  Gene over-expression experiments were conducted in Petunias that were designed to heighten the intensity of color in the flower petals by increasing the level of certain gene products.  This set of experiments resulted in a very surprising outcome.  Instead of gene over expression accentuating the coloration of the flower, the investigators found that the flower petals actually lacked coloration.  Just the opposite of the result anticipated!  The phenomenon was reported in the literature as “co-suppression”[2], but the underlying mechanism remained a mystery.

The explanation came from Fire and Mello’s experiments which identified the culprit for this experimental anomaly as double stranded RNA (dsRNA)[1].  The dsRNA were generated by the expression of both possible RNA strands that could be encoded by the gene (the sense AND the “antisense” strands).  Because they are complementary, the strands actually form a stable double stranded structure akin to the double stranded DNA gene itself.  The resultant dsRNA molecules were able to activate a novel pathway that triggered the destruction of the native mRNA.  This actually reduced the expression of the gene.  They coined the term “RNA interference” to highlight the active molecule and showed that RNAi triggers could be used to down regulate the expression of genes.  Thus, their work provided an explanation for the observations made in Petunias.  This marked the genesis of RNAi, an entire scientific discipline with applications that will fundamentally change science and medicine.

So the next time you participate in any type of an “experiment gone bad” (in the lab or elsewhere), remember, don’t be dogmatic and apply rational logic in a systematic way to resolve the problem.  You might just win a Nobel Prize.

1. Fire, A., et al., Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature, 1998. 391(6669): p. 806-11.
2. Jorgensen, R.A., et al., Chalcone synthase cosuppression phenotypes in petunia flowers: comparison of sense vs.  constructs and single-copy vs. complex T-DNA sequences. Plant Mol Biol, 1996. 31(5): p. 957-73.

 ^ back to top