A few weeks ago, a series of four papers published in Cell provided an early glimpse of a new world of RNA regulation that interacts with microRNAs: competing endogenous RNAs (ceRNA).

All sorts of RNAs – long and short, coding and noncoding – can function as ceRNAs.

They interact when they share target sequences for the same microRNAs, so while microRNAs prevent translation of an RNA transcript into a protein, high levels of ceRNA can hog up the microRNA and increase the levels of other proteins whose messenger RNA has the same ceRNA sequences.

Imagine this: On Halloween, a microRNA zombie axe cuts down all trees it comes across. If that zombie axe is in a forest with equal numbers of oaks and pines, it will cut down an oak about half of the time.

But if the number of oaks suddenly triples, the axe will cut mostly oaks – and one result of that is that there will be more surviving pines, even though the number of oaks in a forest does not by itself influence how many pines there can be.

Hence changes in ceRNA levels can influence the levels of biologically important proteins – such as the tumor suppressor PTEN – as much as changes in the gene for PTEN itself.

Harvard Medical School's Pier Paolo Pandolfi, who first described ceRNAs in 2010, believes that the great majority of RNAs will turn out to be ceRNAs.

With a sum total of fewer than 10 papers published on ceRNAs, to say that much remains to be learned is an understatement.

And the fact the microRNAs have multiple targets is also well known, Regulus Inc.'s chief scientific officer Neil Gibson told BioWorld Insight. Though he added that the new work could ultimately provide insight into whether competition is mainly a numbers game, or whether there are networks of ceRNAs that can drive certain cellular phenotypes

While ceRNAs can be both coding and noncoding, for now it looks like a big part of the importance of the new papers is that they provide a unifying principle for what the more than 90 percent of DNA transcripts that do not get turned into proteins are good for.

"What Pier Paolo has done," explained Jean-Francois Formela, a partner with Atlas Venture, "is to put a stake in the ground and say, 'OK, this is what I think [noncoding RNA] is; this is what I think it does.'"

And whether that stake is in exactly the right spot ultimately matters less than the experimental possibilities it has opened up.

Formela was simultaneously enthusiastic about the discovery's possibilities and levelheaded about what it would take to get from the discovery of a new language to a marketed drug that speaks that language, or shuts it up.

"Some people will go at it as the big thing," he said. "They will say 'It's a whole new language. . . . We're going to change the world.'"

His description of his own response to such enthusiasm has a tough love ring to it: "I would say 'That's great, tell me more! What is your modality, what is your molecule, what is your next experiment?'. . . You need to break it down into what is attainable today."

Issues include sorting out whether a particular form of noncoding RNA is a therapeutic modality or a drug target and what sort of IP protection might be appropriate.

Still, Formela contended the potential of noncoding RNA as a whole could turn out to be truly massive: "It's too early to call," he said.

"But it might be the beginning of the next big cycle of the biopharma industry," Formela added.

With that, one might say that Formela is being a contrarian to much of the pharma world, which has most recently engaged in a rather large-scale retreat from RNAi. Last fall, Roche AG discontinued its preclinical RNAi work, and Novartis AG declined to expand an RNAi partnership with Alnylam Pharmaceuticals Inc. (See BioWorld Today, Sept. 27, 2010, and Nov. 18, 2010.)

But Formela said that this retreat has more to do with issues of "timing, investment expectations and portfolio structuring" than with the underlying value of the approach. He said that at Atlas Venture's recent CEO retreat, one talk compared the timeline of oligonucleotides to monoclonal antibodies – which were also at one point nearly left for dead on the drug development battlefield.

"Oligos are a very young technology," he said. "I would venture to pass on that the chances that there will eventually be a fertile and rich portfolio . . . is very high."

The sheer size of the noncoding RNA universe, he said, makes it a candidate for sustaining not just one company, but, like antibodies, a multifaceted therapeutic approach.

"Nobody will have a monopoly," he said. "There will be so many mechanisms, so many species, so many nuances."