In 2007, the science of RNAi continued to march forward with innovations in delivery, advances in addressing off-target effects, greater use of large-scale screens, and the increase in RNAi-based drugs moving into human testing.
But it was the work done with small, non-coding RNA such as microRNA that topped many industry insiders’ lists of key achievements for the year.
According to John Rossi, a City of Hope researcher and co-founder of RNAi drug companies Calando Pharmaceuticals and Dicerna, “microRNAs continue to be an explosive area of new understanding. The fact of the matter is that they are so important that we can’t ignore them,” he noted.
At the same time, a distinct class of small, regulatory RNA — Piwi-interacting RNA — have landed firmly on the radar screens of the same people who helped make RNAi the subject of Nobel Prize-winning research (see RNAi News, 10/5/2006).
Since little is known about piRNA, “for now [they comprise] a parallel universe” to RNAi, Phil Zamore, Alnylam Pharmaceutical co-founder and University of Massachusetts Medical School researcher, told RNAi News. “But I’m keeping an open mind.
“The [RNAi] field emerged from work done by people who had open minds, which [can be] relatively rare in science, and were willing to say that weird stuff was real and interesting and had biological explanations,” he noted.
Since the discovery of the first miRNA, lin-4, over a decade ago, the small RNA field has grown more rapidly than many would have predicted. Already, miRNAs are being used as biomarkers, with the first miRNA-based cancer diagnostics expected to hit the market later this year (see RNAi News, 8/9/2007). In addition, at least five companies — Rosetta Genomics, Regulus Therapeutics, Miragen Therapeutics, Santaris Pharma, and Stealth Biotech — are actively developing miRNA-targeting drugs.
In 2007, the research linking miRNA to a host of biological processes and disease states — including cancer and cardiovascular health — continued to grow, adding to the body of evidence indicating that these small RNA will prove to be major players in the diagnostic and therapeutic arenas. But the past year also saw greater understanding of other types of small RNA, including the so-called piRNA.
To Zamore, “without a doubt, the [Julius] Brennecke Cell paper was the highlight of the year.”
In that paper, Brennecke and colleagues from Cold Spring Harbor Laboratory reported that piRNA act as “master regulators” of transposon activity in Drosophila
“Our data suggest that heterochromatic piRNA loci interact with potentially active, euchromatic transposons to form an adaptive system for transposon control,” the researchers wrote.
“Without a doubt, the [Julius] Brennecke Cell paper was the highlight of the year.”
“Complementary relationships between sense and antisense piRNA populations suggest an amplification loop wherein each piRNA-directed cleavage event generates the 5' end of a new piRNA,” they added. “Thus, sense piRNAs, formed following cleavage of transposon mRNAs, may enhance production of antisense piRNAs, complementary to active elements, by directing cleavage of transcripts from master control loci.”
“It began really with our own work in 2006, which showed that there was a class of small silencing RNAs that functioned through Argonaute proteins [but] didn’t need Dicer,” Zamore said of the piRNA field. “What that meant suddenly became much clearer, much more exciting with the remarkable work from Brennecke and his colleagues in the Hannon lab.”
Rossi also views advances in the understanding of small regulatory RNA, including work done by University of Texas Southwestern Medical Center investigator David Corey, as a major milestone for 2007.
In a paper published in Nature Chemical Biology in March, Corey and colleagues demonstrated that small duplex RNA targeting chromosomes could both activate or repress gene expression.
“These are the same types of small RNAs that are triggering post-transcriptional gene silencing, yet they can activate up to 20-fold transcription or repress transcription,” Rossi explained. “In either instance, it’s a really fascinating multiple role these small RNAs are playing, [although] what natural mechanism we’re actually capitalizing on when we do these kinds of experiments is still unclear.”
Indeed, “the challenge of connecting mechanism to biology remains for flies, for worms, and especially for mammals,” Zamore noted.
“We’ve done a pretty good job of gathering interesting examples of small RNA biology … [and] as a field, we should be very proud of our efforts to understand mechanism,” he said. “But we haven’t yet connected the two so we can’t say why a given mechanism is being used in a given biological context.”
Ultimately, “the things worth doing are hard, and it takes many iterations before you even get close to the right explanation,” Zamore added. “In biology, the devil is in the details, but also the beauty is in the details because that’s where you start to appreciate the elegance of evolution.”