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A Q&A with Josh Mendell of the McKusick-Nathans Institute of Genetic Medicine who tells how microRNAs are a family affair

You started your lab at Hopkins after having earned a medical degree here in 2003 and a Ph.D. here in 2001. At what point in your science career did microRNAs become the focus?

MENDELL: The field was just starting up in 2003 when I started exploring questions of microRNA biology. At the time, very few microRNAs had been studied in detail. Six years later, we now know that there are at least 500 human microRNAs—maybe as many as 1000—but still the functions of only a handful have been worked out fairly rigorously. I think this aspect of the field really drew me in. MicroRNA research is so rich with fundamental questions. It’s a dream come true to be in a field that’s revolutionizing molecular biology.

Revolutionizing how?

MENDELL: We’re realizing that there is an entire universe of small RNAs being produced in everything from humans to nematode worms, in which microRNAs were discovered 16 years ago. It used to be thought that small RNAs were junk—degraded products of the big important RNAs that have been studied for decades. Only recently have we begun to appreciate an entirely new layer of complexity involving small RNAs and other types of RNA that do not encode proteins. They have incredibly diverse and important functions. They are critical for normal development and cellular homeostasis, and abnormal expression of these molecules has been linked to several diseases, including cancer.

How does your microRNA research relate to cancer?

MENDELL: Cancer cells often exhibit reduced abundance of numerous microRNAs. Sometimes the production of microRNAs is even globally blocked in cancer cells. We set out to test the efficacy of microRNA replacement therapy: We wanted to know if replacing one microRNA in liver tumors in a mouse model could be a feasible, viable therapeutic paradigm. If this strategy could work for cancer, perhaps it could work for other diseases.

Our main question was, if microRNAs are missing from tumor cells, what happens if we put one back? Do the tumor cells die? Do they care? One might expect that replacement of a single small RNA in the setting of all the complex changes that are driving aberrant behavior of a cancer cell might have little effect.

The answer turns out to be yes, the tumor cells in this mouse model are very sensitive to restoration of this microRNA. They die rapidly when it is delivered.

It must be exciting to find out that delivering just one microRNA into a mouse liver engulfed by tumors yields dramatic therapeutic results.

MENDELL: I think we were all amazed at how dramatic the results were. A few years ago it was entirely unclear—and it would have been incredibly surprising to us—that one microRNA could have effects this potent.

Are there any hitches to microRNA replacement therapy?

MENDELL: Delivery of the molecules is going to be a major barrier for applying this technology for therapy in patients. But I don’t think it’s going to be an insurmountable barrier. A lot of great minds are working on this.

Two of whom you’re well-acquainted with, right? This microRNA replacement therapy idea was cooked up around the Mendell table during Thanksgiving dinner? Both your father and wife are also authors of the paper.

MENDELL: This research was a wonderful opportunity for me to collaborate with my dad, Jerry Mendell, whose focus at Ohio State is human gene therapy for neuromuscular diseases. Without his expertise and the expertise of his research group, it would not have been possible to deliver the microRNA. And my wife, Kate O’Donnell, who’s a postdoctoral fellow in Molecular Biology and Genetics here at Hopkins, was integral for her knowledge of the mouse model we used.
By the way, not everybody there at Thanksgiving was appreciating the conversation. But the three of us were really enjoying it. I guess you can view that as either cool or nerdy.

Cool. Very cool!


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