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ESI Special Topic: Gene Silencing
Publication Date: December 2006

Gene Silencing

ESI Special Topics: April 2007
Citing URL: http://esi-topics.com/genesil2006/interviews/PhillipZamore.html

An INTERVIEW with Dr. Phillip Zamore
In the interview below, Special Topics correspondent Gary Taubes talks with Dr. Phillip Zamore about his highly cited work in gene silencing. Dr. Zamore is ranked at #9 in our analysis of the topic, with 23 papers cited a total of 3,805 times. In Essential Science IndicatorsSM, Dr. Zamore’s record includes 35 papers cited a total of 4,540 times to date, the bulk of which are in the field of Molecular Biology & Genetics. Dr. Zamore is the Gretchen Stone Cook Professor of Biomedical Sciences at the University of Massachusetts Medical School in Worcester.

ST:  What prompted the research on double-stranded RNA that led to your highly cited 2000 Cell paper, "RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals" (Zamore PD, et al., Cell 101[1]: 25-33, 31 March 2000)?

I got into this field at very end of my post-doctoral work. The Fire and Mello paper, the one for which Andy and Craig won the Nobel Prize in 2006, came out in March 1998 (Fire A, et al., "Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans," Nature 391: 806-11). I was a post-doc in the Bartel lab at the time. And so was Tom Tuschl. I presented the Fire-Mello paper at journal club, and Tom was giving the experimental progress report for his work, and he proposed an in vitro system for RNAi. He also had finished his post-doctoral work and had secured a faculty position, and so he had some unstructured time ahead of him. Out of the discussions that followed, we decided to attempt the task of developing the in vitro system together. We succeeded in doing that and published it in 1999 in Genes and Development (Tuschl T, et al., "Targeted mRNA degradation by double-stranded RNA in vitro," Genes Dev. 13[24]: 3191-7, 15 December 1999).

ST:  What exactly did your 2000 Cell paper report?

It was the discovery that small RNAs were produced from the double-stranded RNA that triggers RNAi. They act as guides to direct the cleavage of mRNA.

ST:  Why was that so significant?


“In the span of a year, I went from never working on RNAi to having it be the consuming passion of my life.”

We figured out how small RNAs mediate RNAi.

ST:  Was it obvious at the time that this was an incredibly significant discovery?

Yes. We were unbelievably excited. I think our biggest fear was that we would never do anything as exciting again in our lives.

ST:  Did that anxiety turn out to be true? Has there been anything since that was so exciting?

The sensation that you’ve just done your most exciting work can only really happen at the beginning of a really marvelous adventure. So I think that description of it, which I certainly felt at the time, is naïve. Every day that I come to work and learn something new about how small RNA functions in cells is incredibly exciting. But every day is built on the day before. The point is that there were almost no days before that 2000 paper. In the span of a year, I went from never working on RNAi to having it be the consuming passion of my life. I think that’s what happens when you make an important contribution to the field and then continue working in the field.

So while I don’t think I’ve ever been quite as excited as when we were working on that paper, my lab has certainly published a lot of research that I’m awfully proud of and, in many ways, is much more thoughtful. Having said that, the most exciting moment was not that work per se, but rather the day we figured out we had an in vitro system that worked. That was in 1999. When that happened, we knew how much stuff was about to unfold—how much we could do and learn. That technical breakthrough was probably the most exciting thing that ever happened to me.

We did do one other thing that had me every bit as excited at the time. That was a year after I started my own lab and we discovered that Dicer, the enzyme that makes siRNA [silencer RNA], also makes microRNA. That was equally exciting, in part because it was done completely in my own laboratory. That was published in Science in 2001 (Hutvágner G, et al., "A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA," Science 293[5531]: 834-8, 3 August 2001).

ST:  Once you had that in vitro system up and running, was there any anxiety that you might be scooped?

Not until about a month before the 2000 paper. Then we started to hear rumors that Greg Hannon’s laboratory had potentially similar data. Although it turned out to be complementary data, not the same thing.

ST:  What do you think was the most challenging aspect of this research?

Remaining self-critical. Not letting the excitement of the data get in the way of being careful and skeptical about our own interpretations and results. That, by the way, I think is always the hardest part about anything you do that might be important.

ST:  Was there an element of serendipity to your research on RNAi?

The only thing serendipitous was the combination of being in the right place at the right time with the right talents. If figuring out the answer to how RNAi works required being a great cell biologist, we wouldn’t have made a contribution. This was a process in which expertise in the in vitro study of RNA really gives you a leg up, and that we had. But there is no substitute for being in the right place at the right time.

ST:  Since you published your seminal paper in 2000, how has your understanding of these small RNAs developed?

We know a lot more about the proteins involved. We have crystal structures for some of them. We understand that the details are incredibly rich and complex, which reinforced our view and, I think, the general view in the field, that cells devote a considerable amount of energy to small RNA-guided pathways. There are just a lot of proteins involved in making small RNAs, in loading them into complexes, and having these complexes do jobs in the cell.

We have also headed off in other directions. We’ve been trying to understand related small RNA-guided pathways—those that aren’t RNAi but use some of the same components, or related components, but in apparently different ways. These include microRNAs and rasiRNAs, which are the ones involved in silencing transposons. I’m really enjoying that part of our work.

We have continued mechanistic studies of how the RNAi pathway works. That has taken me in some very quantitative directions and keeps reminding me that I should have worked harder when I was taking math in college. We are going to have to become much better biophysicists in the near future. We’ve also started looking at a lot of really cool biology. We’ve found connections between RNAi and lifespan regulation in flies, stem cell biology in flies, and genome stability. That’s an aspect that I never could have anticipated—the incredible depth of biology associated with RNAi.

ST:  So suddenly you’re seeing applications of this research everywhere?

That’s right. That’s part of the reason for the incredibly frantic pace in the field. Suddenly unexplained phenomena and data all over the world are starting to make sense to people when put in the context of this new cellular pathway.

ST:  How does that frenetic pace affect your own life and your own lab?

The main effect for me, personally, is that I’m a lot more tired than I used to be. And I worry a lot more about protecting my students from the pressures of such a competitive field.

ST:  How does one go about creating successful scientists while simultaneously protecting them from the competitive pressures?

It’s just like childrearing and protecting your kids from the scary things in life. It doesn’t mean pretending they don’t exist. It’s giving them the tools to cope with them successfully. For my students, I try to teach them how to be thoughtful in designing and carrying out experiments, so they use their time productively. I also try to foster a spirit of community in the lab, where everyone supports each other. In that way, when the competitive pressures become overwhelming, people can turn to others in the lab for help, both in terms of emotional support and in simply getting help to work on a particular project. This is probably why we always have multiple authors on most of our papers. It puts the science first rather than the ego.

I also try to teach my students to have respect for the other labs in the fields, the labs they’ll end up competing against. It’s important to realize that any competition is secondary to the beauty of the work that the lab does. And one of the wonderful things about our field is that despite the fact that it’s so competitive, there are a lot of really nice people in it, people whose company I enjoy. It makes the research a lot more fun.

ST:  Could this be in part because the field is so fertile and there are so many discoveries to go around?

True. That’s probably because there are still about 100 cookies per lab. When you get into a field where there are 100 labs per cookie, it’s more of a problem. But those fields fix themselves too, because the smart people leave. Nobody should stay in a field like that.

ST:  Five years from now what do you think we’ll have learned about these small RNAs?

I’m pretty sure we’re going to know almost the entire small RNA content of every major model organism plus humans. And we’re going to have crystal structures of most of the major complexes in the pathway. We’re still going to be struggling with describing in detail the molecular interactions and conformational changes that lead to the regulatory events in the various small RNA pathways. I think we will be grappling with that for a long time, since it’s such a hard problem. I think the amount of biology associated with small RNA is going to increase exponentially. People will still be scratching their heads trying to understand why this type of regulatory system is used for so many different things. What’s advantageous about it for the cell?

Also I think there will be a much greater appreciation in the field about the evolutionary significance of making pathways so robust, making them free of noise. Right now there are people who appreciate it, but most molecular biologists don’t think much about the role of reducing noise in bio-regulatory pathways, certainly not in terms of the critical importance for evolution—that organisms able to make their regulatory pathways less noisy are inherently more successful. Although in some circumstances, that noise actually drives evolution forward. Those are areas in which small RNA are going to prove to be really important.

ST:  What do you mean by noise in the context of regulatory pathways?

Regulatory mistakes. For example, cells in which certain genes need to be off 100 percent of the time, but they’re on a very little bit, despite regulatory pathways designed to turn them off. I think there’s growing evidence that this is one of the jobs that RNA does, especially microRNA. It cleans up that noise. It helps make "off" really look like "off."

ST:  If you could do one experiment and funding, time, and resources were no object, what would it be?

Single-molecule studies of conformational dynamics in RNAi pathways. I want to look at a single molecule of RISC, the complex that carries RNAi, and follow it through all the different conformational changes it undergoes to become loaded with small RNA—fully active, bind to target, cut target, and release the piece. Something truly spectacular and unexpected is happening in that cycle.

Once we understand that, we will know why cells have machinery to create RISC. They have whole pathways designed just to assemble RISC, and we’ll understand why the so-called Argonaute proteins are uniquely evolved for small RNA-guided pathways. At the core of every small RNA-guided pathway that’s ever been discovered, there are always these Argonaute proteins holding onto the small RNA and mediating its function. I think those kind of single-molecule studies would tell us why these Argonaute proteins are so special.End

Phillip D. Zamore, Ph.D.
Department of Biochemistry and Molecular Pharmacology
University of Massachusetts Medical School
Worcester, MA, USA

Dr. Phillip Zamore's most-cited paper with 809 cites to date:
Zamore PD, et al., "RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals," Cell 101(1): 25-33, 31 March 2000.

Source: Essential Science Indicators

ESI Special Topics: April 2007
Citing URL: http://esi-topics.com/genesil2006/interviews/PhillipZamore.html

This special topic of Gene Silencing was originally featured in ESI Topics in December 2003. To view the archived Gene Silencing topic, click here.

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