Scientists have recently discovered thousands of active RNA molecules that can control the human body
homas Gingeras did not intend to upend basic ideas about how the human body works. In 2012 the geneticist, now at Cold Spring Harbor Laboratory in New York State, was one of a few hundred colleagues who were simply trying to put together a compendium of human DNA functions. Their project was called ENCODE, for the Encyclopedia of DNA Elements. About a decade earlier almost all of the three billion DNA building blocks that make up the human genome had been identified.
A few noncoding RNAs had been known for many decades, but those seemed to have some role in protein manufacture. For instance, only a few years after Francis Crick, James Watson and several of their colleagues deduced the structure of DNA, researchers found that some RNA, called transfer RNA, grabs onto amino acids that eventually get strung together into proteins.
But now there is no turning back the tide: many thousands of human lncRNAs have been reported, and Mattick suspects the real number is greater than 500,000. Yet only a few of these have been shown to have specific functions, and how many of them really do remains an open question. “I personally don’t think all of those RNAs have an individual role,” Lawrence says. Some, though, may act in groups to regulate other molecules.
Some of these RNAs are not long at all but surprisingly short. Their story began in the 1980s, when Victor Ambros, working as a postdoctoral researcher in the laboratory of biologist Robert Horvitz at the Massachusetts Institute of Technology, was studying a gene denotedcaused developmental defects in which “the cells repeated whole developmental programs that they should have transitioned beyond,” says Ambros, now at the University of Massachusetts Medical School.
One class of small RNAs regulates gene expression by directly interfering with transcription in the cell nucleus, triggering mRNA degradation. These PIWI-interacting RNAs work in conjunction with a class of proteins called PIWI Argonautes. PiRNAs operate in germline cells , where they combat “selfish” DNA sequences called transposons or “jumping genes”: sequences that can insert copies of themselves throughout the genome in a disruptive way.
Yet a problem with using small RNAs as drugs is that they elicit an immune response. Precisely because the immune system aims to protect against viral RNA, it usually recognizes and attacks any “nonself” RNA. One strategy for protecting therapeutic RNA from immune assault and degradation is to chemically modify its backbone so that it forms a nonnatural “locked” ring structure that the degrading enzymes can’t easily recognize.
Brennecke advises caution about current high estimates of the number of noncoding genes. Although he agrees that such genes “have been underappreciated for a long time,” he says we should not leap to assuming that all lncRNAs have functions. Many of them are transcribed only at low levels, which is what one would expect if indeed they were just random noise.
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