Finding the Missing "Linc"
The Story Behind the Science
website of scientist John Rinn offers browsers a number of options: Click here for Research; click here for Publications; click here for Contacts/Lincs. Wait, shouldn't that be spelled Links?
No, it's not a typo, but a bit of scientific wordplay: "Linc" is an acronym for Large Intergenic Non-Coding RNA, a new class of molecule gaining attention in the field of genomics. And for Rinn, an investigator in BIDMC's Department of Pathology, lincs are the primary focus of his work.
In the February 1, 2009 on-line issue of the scientific journal Nature Rinn, together with genomics pioneer Eric Lander, founding director of the Broad Institute, describe their discovery of more than 1,000 functional
lincRNA molecules in mammals. Using a novel means of analysis, the scientists have uncovered a set of genetic elements that could one day lead to new avenues for developing therapeutics, particularly in cancers.
As Lander puts it, "We've known that the human genome still has many tricks up its sleeve. But it is astounding to realize that there is a huge class of RNA-based genes that we have almost entirely missed until now."
In late January 2009, Rinn was one of three scientists from among nearly 300 applicants nationwide to be awarded the
2009 Damon Runyon-Rachleff Innovation Award by the Damon Runyon Cancer Research Foundation. Focusing on projects that involve high risk - and high reward -- Rinn's dogged pursuit of these mysterious molecules fit the bill. The three year $450,000 prize is made to early-career researchers who are using "novel approaches to fighting cancer," an apt description for Rinn's willingness to challenge traditional scientific thinking.
The Search for the Missing "Linc"
You might say that lincRNAs are Rinn's own genetic Holy Grail. Once dismissed as genomic "junk," these RNA molecules had neither a name nor identity. But that didn't dissuade Rinn from learning more about them.
"Ever since my first project in graduate school I decided I wanted to know what these mysterious creatures do," says Rinn. "There were thousands of them and even though none of them appeared to have any function, I always thought they must have a biologically meaningful purpose."
His conviction was not widely shared. Without evidence to the contrary, the theory that these inexplicable molecules were more than just"filler" was dismissed by much of the scientific community.
So, after joining the laboratory of Howard Chang at Stanford University as a postdoctoral fellow, Rinn set out to hunt down just one functional example to show that lincRNA molecules were anything but superfluous.
Finding the Missing "Linc"
Six years after graduate school - and his first observations of these RNA molecules - Rinn says his discovery of the lincRNA that came to be known as HOTAIR was "like striking a gold mine."
As it turned out, HOTAIR had an important function, establishing a genetic code in skin cells. "Among skin cells, HOTAIR was serving as something of a genetic GPS system, guiding the cells to their correct destinations in the body, be it the finger, the foot, or the foreskin, for example," says Rinn. "This particular lincRNA molecule was regulating a part of a 'skin code' that indicated what they should be doing."
His prospecting quest now bolstered by this discovery, Rinn theorized that perhaps some of the other as-yet-unidentified lincRNAs were serving similar functions. "How is it that the very same genome that exists in each and every one of our body's cells can serve vastly different purposes depending on its location in the body?" he wondered "How does it know whether to become a brain cell, a heart cell, a liver cell or a skin cell?"
In the study published in Nature, by examining these molecules in a new way, Rinn and his coauthors were able to "sift" out still more genomic gold - more than 1,000 previously unknown
lincRNAs. "They were hiding in plain sight," says Rinn.
Using the funding from the Damon Runyon Cancer Research Foundation, Rinn will press on to further understand how lincRNAs play a role in health and disease, cancer in particular.
"This is a very powerful mechanism of genomic organization and has a lot of potential for cancer therapeutics," says Rinn. "If we can solve the code of how each lincRNA knows what part of the genome to regulate, we might be able to exploit this mechanism to engineer lincRNAs that 'fix' a damaged cancer genome by targeting and silencing overactive cancer cells, thereby restoring the genome back to its proper identity."