"It fell straight down, why was that?" - Issac Newton

RNAi started off as a series of accidental discoveries, that started with some plant geneticists trying to mutate their purple petunias in the 1990s.

They wanted to overexpress a gene that the petunia naturally had--an enzyme responsible for production of purple pigments in the flowers. To do so, they created a chimeric gene or transgene (chimera sounds cooler though), that consisted of the purple protein expressing gene fused to a viral promoter (35S), which would force the expression of the gene in spite of any natural inhibitors the plant would have. The result would be maybe an interesting shade of purple or one steady-state of purple, supporting the hypothesis that the numbers of protein would send "brain waves" to the plant to some how limit the amount of purple being made in the flowers. Instead, they got albino flowers and some purple flowers with patches of white.

For whatever reason, introducing a transgene with a copy of a gene normally expressed by a petunia, caused the silencing of both the transgene and the endogenous gene. (Even if the transgene was malfunctioning, the endogenous gene naturally in the petunia should have been working and supplying purple making proteins, but oddly, both shut down or weren't express at all.) They realized something was going on with the system, some new mechanism triggered by introducing a copy of the endogenous gene that caused both to lose their normal roles in making petunia flowers purple.

After more "accidental" discoveries in other organisms, especially in worms and Arabidopsis, researchers unraveled the mysterious mechanism--RNAi. Where any expressed gene that produces RNAs with antisense or inverse complementarity to another "target" gene causes the formation of an RNA silencing complex (RISC) of proteins that in turn, degrades the mRNAs of the other gene or stops the production of of its proteins. Naturally, all organisms appear to have natural microRNAs, 21 nucleotides long RNAs encoded by their own genes to halt the protein production directed by other genes. Plants use the RISC proteins as a defense against viruses, by reducing viral RNA or expressed DNA into 18-22 nucleotides long short interfering RNAs (siRNAs) that can be used by RISC to further degrade other viral RNAs.

10 years later, RNAi's become a seriously bankable type of biotechnology, with implications in crop defense against viruses, human diseases and even stem cell research.

However, some might say that scientists have been noticing the odd defense mechanisms of plants against viruses for decades, at least right up to 1928. But, this was before the notion of genes and RNAs. Sometimes it requires the right background knowledge, technology, experiment and the right person and in the right place to find the accident that changes everything.

----- Articles:

Voinnet O. RNA silencing as a plant immune system against viruses. _Trends in Genetics_ *17*(8), 449-459 (2001). doi:10.1016/S0168-9525(01)02367-8

Baulcombe D. RNA silencing in plants. _Nature_ *431*, 356-363 (2004). doi:10.1038/nature02874

Napoli C., Lemieux C. and R. Jorgensen. Introduction of a Chimeric Chalcone Synthase gene into petunia results in Reversible Co-Suppression of homologous genes in trans. _The Plant Cell_*2*(4), 279-289 (1990). http://www.plantcell.org/cgi/content/abstract/2/4/279

Lee R. C., Feinbaum R. L., and V. Ambros. The C. elegans Heterochronic Gene _lin-4_ encodes small RNAs with Antisense complementarity to _lin-14_. _The Cell_*75*, 843-854 (1993). http://www.blatny.com/Epigenetika2007/2007-12-04/papers/Lee%201993.pdf

Listening to: You know my name by Chris Cornell (Casino Royale OST Track)