The Gene Silencer

From the “organized chaos” of Dr. Gregory Hannon’s laboratory, new ways of studying the evolution of cancer are emerging.
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TRANSCRIPT

Question: How does your lab typically operate?

Gregory Hannon: Sure.  The lab is sort of organized chaos.  There are about 35 or 40 people in it.  Graduate students, post-doctoral fellows, technicians, support staff, etc.  We have probably an unusually broad research program.  We focus in on three major areas.  We work on the biology of small RNAs, we work on cancer biology, usually with the roles of the small RNAs in cancer and ways in which we can use small RNAs to understand cancer.  And then we have a third area, which is technology development and genomics and mostly making use of some new generation sequencing technologies to try to understand everything from the evolution of cancer to human evolution.

Question: What is RNA interference?

Gregory Hannon: Well, RNA interference actually now describes a fairly broad range of biological phenomena.  The notion is that RNA has a sequence just like DNA does.  So then that sequence can be used to recognize complementary RNAs that share the sort of inverse of that sequence, the image of that sequence if you want to think of it that way.  And through that recognition, a lot of jobs can be done.  The RNAs recognized can be destroyed, they can be taken to different places in the cell, or they can even guide processes as strange as taking pieces out of the genome, depending on what organism you are talking about.

Question: How can RNA interference be used to “silence” genes in living cells?

Gregory Hannon: The evolutionarily deepest role of RNAi is as a genome defense.  It’s a way that plants, for example, recognize and fight viruses.  It’s a way that animals recognize parasitic pieces of DNA within their genomes, called transposons, and shut those off.  It’s also a way that the cell uses RNA to program the regulation of its own genes, and we can exploit any one of these responses, essentially tricking the RNAi machinery into silencing any gene that we want just by fooling the machinery into recognizing it as, in essence, one of these foreign elements.  And we can use that for a number of purposes.  The one we mainly use it for is for trying to understand the biology of those genes.  And again, in our case, mostly trying to understand what different sets of genes do in tumor development.

Question: What experiments have you performed to investigate the role of the RNAi pathway in animals?

Gregory Hannon: We’ve done a number of experiments in mice to try to figure out really, what RNAi does in animals, and I can give you a couple of examples.  One is, we’ve looked at the small RNAs that the cell makes in order to regulate its own genes and compared the spectrum of those small RNAs in normal cells versus tumor cells.

In one of the first cases that we did this was in a tumor type called D-cell lymphoma.   And by making that comparison, we discovered that there were a set of micro-RNAs, which is what these endogenous small RNAs are called.  They’re different between the normal cells and the tumor cells.  It turns out that that locust, that gene which encodes those micro-RNAs is often amplified in that specific tumor type.  And if we reproduce that event, adding extra copies of that micro-RNA gene, we actually accelerate the development of that particular tumor in mice.

Another way we approach this problem is by taking all of the components of the RNAi machinery, all the proteins that actually bind to the small RNAs and that the small RNAs programmed to do these regulatory events and delete them from the genome and ask what the consequences are.  And it was in part those experiments that led us to the realization that RNAi in animals placed this sort of genome defensive role, protecting the DNA of germ cells from the ravages of these mobile genetic elements called transposons.

Recorded on February 9, 2010

Interviewed by Austin Allen