Job title:Assistant Professor of Pathology
Location:Harvard Medical School/Beth Israel Deaconess Medical Center/Broad Institute, Cambridge, MA
 How do you explain your job at cocktail parties?
By way of analogy, I might describe our work as “genomic origami.” A flat piece of paper can be transformed into numerous three-dimensional structures such as a crane or a paper airplane (my favorite), all through a progression of folds. Similarly, we can imagine the genome undergoing a series of folds that produce distinctive genomic landscapes that define cellular function. It’s remarkable to think the same genome sequence is present in every single cell of our body, yet it’s the alternate conformations the genome undergoes that create the differences between a liver, kidney, or brain cell.
Our research aims to understand the role of large non-coding RNA genes in molding cellular identity. “Non-coding” RNA isn’t used for manufacturing proteins, the workhorses of cellular biology—but it can still greatly influence cells. For example, a single large non-coding RNA gene can shut off most of the X chromosome. Through complex choreography, this RNA gene associates with a genome-folding complex and spreads to essentially crumple the chromosome. Our work has identified hundreds of other RNA genes that may play similar roles in “landscaping” the genome. We aim to understand the mechanism by which RNA molecules interact with key protein complexes to establish and maintain the genomic architectures of distinct cell fates such as stem cells. Moreover, we are investigating how these genes are misshaped in cancer, and how to potentially refold genomes. Going back to the origami metaphor if just one of the wings, or a flap in the genome becomes misfolded it can result in cancer.
 In the past six months, what has been the most exciting advance or breakthrough you’ve had in the lab?
One of the most exciting advances in the lab recently has been finding novel large RNA genes in the vast spaces of the genome in between classic protein coding genes termed large intervening non-coding RNAs (lincRNAs)—the “missing links of the genome”—play a role in orchestrating genome-folding complexes. It appears that ribonucleic-protein interactions are quite rampant throughout the nucleus, and we are excited to resolve their functional importance and the logic behind them. I suspect this may represent an RNA-based “traffic control system” for proteins. The same way thousands of planes are organized each day by air-traffic controllers, RNA may be playing a similar role in the nucleus, guiding proteins to their proper destination.
 Complete this sentence: We could make huge strides in the field, if we could just figure out…
…all the mysterious roles RNA plays in regulating the fate of cells. These large RNA genes represent a relatively unexplored class of genetic elements that herald a whole new paradigm in our understanding of genome biology. As an example, we need to figure out how large non-coding RNAs play a role in imparting specific genomic architectures (such as making creases in the genome). If we crack this problem, we could envision bending the genome to our will and engineering specific cell types. More importantly we could possibly design RNA molecules to target and deactivate overactive genes in cancer. Although there are numerous challenges ahead, the ends certainly motivate the means.
 What’s the biggest misconception about your field?
That most of the genome is junk. I am not saying it’s all relevant, but I think it’s inaccurate to term something “junk” unless it is proven so; negative results are singularities in experimental science. In other words “an absence of evidence is not evidence of absence,” as the expression goes. So until each and every region has had a fair chance to be tested we shouldn’t dismiss them as junk.
 Scientist and non-scientist you’d most like to meet?
Scientist: Jean-Baptiste Lamarck, an early French proponent of evolution. I think his theory of “soft inheritance,” that organisms can pass on characteristics acquired during their lifetime to offspring, was underappreciated. I would like to hear his thoughts on the potential roles of maternal/paternal transfer of RNA to relay environmental information.
Non-scientist: Steve Prefontaine, my lifetime hero. We would need a long run!
 What are you reading now?
Good to Great by Jim Collins. I was hooked by the sentence: “The enemy of great is good.” Other than that, perhaps most of my nonscientific reading occurs perusing snowboarding and skateboarding magazines with a cup of coffee at a bookstore. The way these athletes push boundaries inspires me scientifically.
Before finding science I was actually focused on a snowboarding and skateboarding career, and academics took a backseat to those loves at that time. But several severe injuries, an influential book, and a consequent shift in perspective changed that path dramatically. I now see risk-taking science as similar to skating or boarding. “Go big, or get hurt,” as we say. Practicing tricks over and over is like an experiment. Moreover, connecting a series of tricks down a mountain or while skateboarding for a beautiful run is a metaphor to me for connecting various lines of experimental results.
 When I was a child, I wanted to be…
An Olympic runner or hockey player. The pursuit of these passions has been my most profound educational experience of all.
 What advice would you give someone just starting out in your field?
Learn to write and speak, not just to crunch numbers. Whether you can get your message across is as important as the message itself.
 If the NSF surprised you with a $2 million grant tomorrow, what would you spend it on?
Ants and bees. Social insects fascinate me, and I have a hunch that maternal and/or paternal RNA storage may be involved in establishing which larvae becomes a worker or a queen. More practically, I would use the money to perform combinatorial genetic engineering of stem cells, aiming to guide and tweak their metamorphoses into other types of cells.
 Why do you do science? What inspires you?
I have tried almost everything else, and science is my lifeblood. The unknown and the consequent possibilities inspire me. Working with such creative and talented people everyday makes all the hardships worth it.
Originally published March 22, 2010