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MIT s Luk Van Parijs Discusses RNAi and the Genetic Basis of Disease

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Name: Luk Van Parijs

Position: Assistant Professor at MIT’s Center for Cancer Research

Background: BA with honors, natural sciences, University of Cambridge — 1991 PhD, immunology, Harvard University — 1997 Assistant professor, MIT — 2000-present

Growing up in Belgium and pursuing his university studies in England, Luk Van Parijs came to the US to do his graduate work at Harvard University. Now, as an assistant professor at MIT’s Center for Cancer Research, he appears to be here to stay, for a while anyway, as he researches the molecular and genetic foundations of immune system responses and diseases. RNAi News recently spoke to Van Parijs to discuss his work and the role of RNAi in it.

How did you get involved with RNAi?

The Center for Cancer Research has been one of the pioneering institutions for this work, and we were lucky enough to have close collaborations with Phil Sharp. [MIT] is where a lot of his initial discoveries were made, and that’s really how we got into it — applying this obviously very powerful technology to the biological questions we were interested in.

Can you give an overview of the work you’re doing now and the role of RNA interference?

What we’re really focused on is to use high-throughput RNAi as a tool to understand the genetics of complicated immunological diseases. Particularly, we’re interested in immune cancers and autoimmune disease. So, our major focus is to use RNAi to look in vivo, so in mouse models of disease, [at] what genes are contributing to the disease process.

In the context of RNAi, the major goal for us — and I think this is sort of a fairly new idea, or at least executing it — is to say: we know RNAi is powerful, and we know we have some pretty impressive expression systems. … [Let’s] try, in a very systematic way, to look at the genetics of complicated biological processes. I think that’s what most of our interesting, novel efforts are. For the rest, we’re using RNAi like many people are: to validate genes doing things in particular situations. But I think that really taking an animal and saying: can I look, using RNAi, for new genes that will control particular diseases, is a pretty exciting new direction.

What sort of things have you found thus far?

What we’ve accomplished, and [what] I think [is] our most significant accomplishment, has been to generate a lentivirus-based expression system that allows RNAi to be induced really in pretty much any tissue you’re interested in. Now, we’ve sort of coupled that with a generation of shRNA libraries to look for genetic interactions in vivo between oncogenes and potential tumor suppressors, or other oncogenes that control cancer.

So, what we’ve done is basically screen for genes that act either with or against a specific oncogene called c-Myc to control the development of cancer in the immune system. What we’ve found is, perhaps not surprisingly, we’re pulling out novel genes, pro-apoptotic genes, that antagonize c-Myc-induced tumerogenesis. So, anything that’s going to induce apoptosis, going to slow down tumor formation — if we silence those genes with RNAi we get faster tumors.

Conversely, we’re also finding oncogenes, such as Akt, which actually interact with c-Myc to promote tumorogenesis. So, when we silence those with short hairpins, we’re finding that we sort of suppress tumors. And the idea here is that this is a very efficient strategy to not only identify genetic interactions that are important in cancer — and we’re also doing some work in autoimmune disease — but by structuring the library of short hairpins that we use appropriately, we could even make this a fast step towards target validation for therapeutics.

Could you talk about the vector you developed?

It was clear, once the fact was established that you could express a short hairpin RNA in a cell of interest and induce RNAi, that the trick really was going to be: what’s the most flexible system available to express short hairpin RNAs? And we were particularly interested in primary cells and tissues and mice — you know, experimental model systems. So, we were not particularly concerned about being able to express the short hairpins just in tissue culture cells — we really wanted to do this in vivo, in animals.

At the time we started, and I think still now, the only really flexible expression system to do this stuff in are lentiviral vectors. And that’s because they can pretty much infect any cell, including stem cells, and once they infect a stem cell, they induce stable integration and stable expression of whatever you’re expressing, including a short hairpin.

That stem cell, when it develops, will continue to express that short hairpin. So, the idea was that if we can infect with our lentiviruses embryos or hemtapoietic stem cells, then we can express short hairpins in every single cell that derives from those cells, and we can get RNAi induced in all the tissues that result.

Are you satisfied with the vectors? Are they still being refined?

So, the refinements that are ongoing — the published vectors basically express a short hairpin RNA under a constitutive promoter — the U6 promoter or the H1 promoter. The recent developments that my lab has been working on, and other labs are, is to basically [do] two things: first of all, getting regulated expression of short hairpin RNAs. There are a number of ways to do that, but one of the ways that this has been done is by putting the U6 promoter under the control of tetracycline, a small molecule.

The second major advance is to get tissue specific short hairpin RNA expression — so, only in T-lymphocytes, for example, or only in the brain or only in the pancreas. And that’s being done by figuring out how we can use tissue-specific promoters to drive the efficient expression of short hairpin RNAs.

Cancer is one area you are looking at, but you also mentioned autoimmune disease. What kinds?

We’re particularly interested in diabetes. There are actually a couple of very good animal models for diabetes, and these are genetically very complicated. So, we’re trying to use high-throughput, or at least reasonably high-throughput, RNAi approaches to systematically go through either target genes, or to find new genes that control diabetes.

What I mean by target genes is that a number of people have already used genetic approaches to identify genes that they think are involved [in diabetes]. However, none of those genes have been directly validated just because it’s a real pain in the butt to actually do those experiments. It’s very difficult to do this in a systematic fashion. So, what we’re doing is systematically going through all the genes that people have predicted might be involved in diabetes. But I think [what is] even more exciting is that we’re using short hairpin RNA libraries to look for genes that convert normal mice into mice that get diabetes, or vice versa.

Once you have identified certain genes and you’ve collected these data, will they be released publicly?

Absolutely. Our interest is largely in understanding the mechanisms that control the normal and diseased regulation of the immune system. We’re in the process of preparing a number of these for publication, and the plan is to systematically screen through families of genes to find … their contribution to these complicated biological processes. Hopefully, [we’ll] be able to build up a much better understanding of how these diseases originate and how we might be able to treat them.

Any possibility of, or existing, industry partnerships?

Actually, the cancer screen has been done in close collaboration with people over at Serono. And I think that, given the nature of these experiments, there’s not only a large interest from industry, there’s also funds and the sort of set-up that is particularly well-suited for industrial partners to help with.

This work is great for identifying targets for small molecule drugs. What about actual RNAi drugs?

I think, like probably many people [do], that it’s hard to see, at this stage, how it’s going to become a terribly viable therapeutics strategy.

There’s two things. We deal a lot with gene therapy-based strategies. These lentiviral vectors we use are basically modifications of vectors that are at least being developed for human gene therapy. Using these in actual therapeutic settings, there are many, many hurdles to overcome, and those hurdles may be too high. The major ones are that when you infect the given cell with these vectors, these vectors will go and integrate anywhere into the genome, which may include a critical gene for normal function or a disease-regulating gene. It is well-established that these gene therapy vectors have a chance of inducing leukemias and other types of diseases themselves.

So, that makes it hard to imagine how you’d use the lentiviral RNAi approach as a therapeutic. Now, to use siRNAs as therapeutics has substantial limitations, too, which are largely related to delivery. So, it’s hard, at this stage, to see whether or not RNAi-based strategies are going to be developed as therapeutics directly.

[MIT’s Spectrum] mentioned that you learned a lot of English from television. Any particular show?

I have to say, when people ask me, Knight Rider was pretty high up on the list … much to my chagrin.

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