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UMDNJ s Eric Moss on microRNAs and What Is Left to Learn

Eric Moss
Associate professor, molecular biology
University of Medicine and Dentistry of
New Jersey

Name: Eric Moss

Position: Associate professor, molecular biology, University of Medicine and Dentistry of New Jersey

Background: Associate member, Fox Chase Cancer Center — 1997-2003

Postdoc, Harvard University — 1991-1997

PhD, microbiology, Columbia University — 1991

BS, microbiology, University of Rochester — 1984

After playing a part in the early days of microRNAs as a postdoc in Victor Ambros' lab at Harvard University, Eric Moss has continued working in the field at the University of Medicine and Dentistry of New Jersey as part of a broader focus on developmental timing.

Recently, he spoke with RNAi News about his lab, his research, and his thoughts on the miRNA field in general.

How about a general overview of your lab?

I think of myself primarily as a molecular developmental biologist — I'm interested in molecular mechanisms that control development. I went to Victor Ambros' lab [as a postdoc] because he had this unique angle; he had these developmental timing mutants. I was and am primarily interested in that developmental process. He identified a series of mutants — lin-4, lin-14, lin-28, and so on — that caused unusual phenotypes in worms, and there were no similar phenotypes in any other animals including the fly, which is studied very extensively for its development phenotypes.

I thought that was very interesting and wanted to work on that, and that's what I'm continuing to do. I want to understand how developmental timing decisions are made [and] not only in worms. … What happened at Fox Chase was that we started looking for homologs of heterochronic genes outside of worms, and for many of the people in the field that had been unsuccessful. Lin-14, for example, has no homolog in any other organism.

We had found lin-28 in Drosophila and then started working out from there. It was at the same time that Gary Ruvkun's group had identified let-7 and found that that microRNA had homologs, so that was the other member of this pathway that had homologs outside of C. elegans. … That was very cool — we had these two genes, let-7 and lin-28, that had homologs.

My lab continues to pursue the role of lin-28 in mammals, as well [as in C. elegans.] It's a small RNA-binding protein, and when we found that it's targeted by microRNAs in mammals we recognized the relationship between lin-28 and microRNAs was conserved, which gives us clues as to what its role might be.

So that's what we're doing. We study other RNA-binding proteins as well, and other aspects of worm development, but the focus of the lab is still on developmental timing, particularly the role of lin-28 in developmental timing decisions in worms and in mammals.

Where are you in your thinking about that at this point?

The microRNA field is kind of muddled and conflicted. I think there was a lot of work to find the microRNAs, and it's very clear that the genomes of people have hundreds of these things. Then, there was this effort to find targets using the rules that were established based on lin-14 and lin-28. … But what we knew about the pathway from C. elegans is that it's not as simple as a single microRNA down-regulating a single target, and maybe it's becoming clearer now that there are multiple microRNAs attacking single targets and multiple targets for single microRNAs.

But it's very hard to figure out from the mammalian stuff … what [microRNAs] are doing. Why [do you] have these microRNAs, when you have transcriptional regulation on the very same genes? In the worm, where we have a lot more information, my thinking is microRNAs aren't just tweakers of gene expression, as some people might suggest … but [they] … play critical roles in transitions in pathways — controlling dynamics of events, and that's very hard to witness as a strict molecular biologist working in mammalian systems. That's why C. elegans genetics is so powerful — you can see multiple components of the pathway working simultaneously and you can see it on the phenotypic level very well. So my thinking is that people aren't seeing what microRNAs are doing in mammals because they are working at a very fine scale that people aren't used to working at.

Are we just limited by existing tools?

Of course. That's it. We're limited by tools and limited by patience. You're not going to figure out what microRNAs are doing using microarrays very easily, and that's the way people want to work now.

There's another whole side debate going on about how microRNAs work. What's the molecular mechanism? Victor [Ambros] and I published papers some time ago claiming lin-4 was working by a mechanism that didn't change the mRNA level. That became widely held and there were a number of people who supported that from the mammalian point of view — Phil Sharp was one of them.

This is a big issue for people who are interested in siRNAs and who are interested in using microarrays. If you have this gene regulator changing the activity of a gene by affecting protein production, but you can't witness that at the level of an mRNA change, that's serious. Affymetrix wouldn't like that. But now there's been this sort of backlash: There was a highly publicized paper out of Amy Pasquinelli's lab that [suggested], 'No, no. Moss and Ambros were both wrong,' although it didn't quite say that. I think this really requires revisiting because she's claiming that [microRNAs do] cause [mRNA] degradation. You'll hear about this, that microRNAs can cause cleavage, [although] we know that they don't cause cleavage in the same way that siRNAs do, and I think that this issue has to be addressed. It might not be the same for every gene and that's okay for me — I can see microRNAs acting in different ways on different genes.

That's a mechanistic issue that's hard to get at. I think we're limited by technology and patience. It will take somebody really rolling up their sleeves — not that people haven't tried — [and developing] an in vitro system for how microRNAs work. Obviously, [Tom] Tuschl and [Phil] Zamore brilliantly created this system for siRNAs — that's what really exploded the whole field — but those systems don't recapitulate how animal microRNAs work. That, from what I can tell, still doesn't exist, and all attempts to try to figure out the mechanism of microRNAs have really been indirect — and that's what's fueled this controversy about how they work.

That's a true scientific limitation. I think for many people who are interested in how microRNAs affect [a particular] disease, relying on microarrays is going to be quite limiting. I don't really work in that field — I'm still a one-gene-at-a-time kind of guy. I think there's still a lot to be learned that way, but the world is moving in a different direction.

[Working with single genes is] not going to get you all the answers right away.

People want answers. They don't necessarily want the right answers, they just want answers, so that's why genome-wide this or that is so appealing. I think it's been shown again and again, especially when you're dealing with something like the heterochronic pathway in C. elegans, that your expectations can be overturned — you think something is working in a way that you have circumstantial evidence [supporting it], but then you go a little deeper or something else pops up and you say, 'Oh, that's not the way it's working at all.' We're finding out that lin-14 and lin-28 are actually targeted by multiple microRNAs — we didn't even know that before. Victor Ambros worked out his whole [microRNA] pathway, and he was perfectly right in all the things he predicted, just using genetics without any understanding of the molecular mechanisms because he hadn't cloned the genes at that point. But, we see now, he was only working with skeleton components of the pathway — just a few of what are turning out to be a dozen or more components of this pathway.

If you have the patience, you can go a little deeper and find out how things are actually working. …I think people will find out that the microRNAs, like anything else, even transcription factors, are involved in much more complex pathways than this sort of one-microRNA, one-target paradigm would have you believe. …

I'm very bullish on this. I think when people figure out how [microRNAs] work, they can tap into very important aspects of biology that we haven't had access to. But, I think there's sort of this post-modernism that's taken over where we think that all the paradigms in biology are known already — we know all the genes, we know all the pathways, and we know how it all works, so we just have to push on technology and we can manipulate it. My feeling is that you can get this false sense of things if you just read review articles, if you just read textbooks. People don't talk about what isn't known, and I think microRNAs are a great example of that from a number of points of view. First of all, as Phil Sharp and others have said, 'I can't believe we missed this.' MicroRNAs are involved in so many things, and yet nobody knew they were there. … That's one thing — there are still more surprises.

The other thing is that you just have to look at genome annotation. Take your favorite gene, one that you know something about, and look how it gets annotated in a genome and you see this annotation is sometimes up to 50 percent wrong. Anybody who's using this as received wisdom is going to be led astray. There are enormous amounts of things that are not known, and that's just the nature of the enterprise. People need to keep the funding coming and they have to create a false sense of expertise in certain areas. But I'm excited that there's so much left to learn, not only about how microRNAs work at the mechanistic level, but how they're working to control the biology of the animal — I don't think we have any good purchase on that yet. We have a couple of really good examples, but even those are incomplete.

What are all these microRNAs doing? When we figure that out, we'll have something to tap into, and that's something people can look forward to, but we're not there yet. Hopefully, the people who fund the basic research will see that too.

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