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Cenix s Chris Echeverri on Leaving Academia to Run an RNAi Company


At A Glance

Name: Chris Echeverri

Position: Co-founder, CEO, CSO, Cenix Bioscience

Background: Postdoc, EMBL — 1998-1999; PhD, cell biology, University of Massachusetts Medical School — 1998; MS, biology, University of Ottawa — 1992; BS, biology, University of Ottawa — 1990

Though coming from the world of academia, Chris Echeverri has seemingly had little trouble adapting to his role as chief executive at Cenix Bioscience. Recently, Echeverri spoke with RNAi News about his unusual career path and where the company is headed.

How did you get involved with RNAi?

I first got involved in RNAi when I started my postdoc in Tony Hyman’s lab at the EMBL in Heidelberg. I arrived there in February 1998 after finishing my PhD at the UMass Medical School in Worcester, which is a little bit ironic because I had just left one of the two birthplaces of RNAi in C. elegans, namely Craig Mello’s lab.

I went to Tony Hyman’s lab to study kinetochore function using C. elegans, and Tony had another postdoc there by the name of Pierre Gonczy, who had been using the C. elegans system to look at microtubule-based processes for awhile during the early embryonic divisions. It took them a few months to convince me of the wisdom of trying out this new method of gene silencing, not just on a handful of genes but literally at the genome scale, as a new screening method. [This] at first to me sounded crazy, and the people we asked at the time agreed that it was a crazy idea.

After enough beers and enough coffees, after a few months, Tony and Pierre managed to convince me to take this on as my postdoc project. So the work started in September 1998 and I’ve never looked back.

How did things get going with Max Planck to the point where Cenix was born?

Tony at the time was cross-appointed both as a group leader at the EMBL and one of the five directors of a new Max Planck Institute that was being built in Dresden. He knew that once the building in Dresden was completed, he would move there.

The [RNAi] project … was co-directed by Pierre and myself, and involved a group of about nine or 10 people in Tony’s lab. It was a pilot, which was meant to focus on one of the six chromosomes in C. elegans. [By] applying RNAi, [we wanted to] see if we could scale up the technology robustly enough that we could apply it systematically to these approximately 2,300 genes of chromosome three, focusing specifically on trying to identify genes involved in cell division.

By the summer of 1999, it was clear this was working, so the question was: How will we go beyond this to look at the rest of the genome. Of course, we realized that if this worked this well in C. elegans, it would be fascinating to see if this could be applied in other systems in a much broader way. We knew already then if it could be applied in other systems, it would change radically how genes are discovered and characterized, especially for therapeutic development purposes.

It was brought to our attention that it would be wise to consider pursuing this whole concept not in academia but in industry as a venture capital-backed start-up company, so that we could get enough resources — enough money, basically — to be able to focus on this and build it up on the scale we thought was needed.

Pierre and Tony had already committed to staying in academia by then. We knew that if we were going to do this company, one of us would have to leave academia and get involved directly in operations to build up the company, at least for the first few years. I was the only one of the three who was in a position to leave academia and get involved directly in operations of the company. I had never ever considered leaving academia before this, so I certainly hesitated quite a bit. After considering all the pros and cons, in the end, I considered this a unique opportunity and a unique challenge, and I would probably hate myself forever if I didn’t try it.

I chose to go ahead and jump into the project and start the company. That was the summer of 1999.

You had said that the plan, at least initially, was that you’d come in to the company and help get it up and running, then eventually phase yourself out. Is that still the plan?

That’s a good question. This October, we’ll be celebrating Cenix’s fifth birthday and to be perfectly honest, I didn’t expect that I’d still be involved in operations after five years. I had expected after two or three years I would hand it off to people who know what they’re doing and I’d move on, whether to industry or academia, I wasn’t really set.

I’m very happy [at Cenix]. It’s been an amazing ride — certainly a huge learning experience for me. It has stretched me in new directions along the way. Whether I continue being involved in operations going forward will really depend on the shareholders and the staff to decide.

I’m not ruling out any options.

As it stands now, though, we shouldn’t expect to see a change in the near term. You’re pretty happy where you are.

Yes. I am happy and I’m not planning any changes, but of course, my opinion is not the only one that matters.

You would consider, then, returning to academia.

Absolutely. There’s a big part of me that’s most motivated by the pure science of what we do here. The management aspects, the organizational aspects, building up an operations and motivating a group, getting it organized, doing my best to put all the pieces together such that we generate very high quality research — it’s fascinating, it’s a thrill. But the for-profit aspect of it is not something that I desperately need. I could completely see myself going back to a non-profit world.

What would you say was the toughest part of coming as a researcher and being put in charge of ramping up a company like Cenix?

The training I got as an academic researcher certainly prepared me for learning how to design experiments, how to conduct experiments properly, how to pose the right questions, how to test them properly, how to evaluate other people’s work, and also how to collaborate with others and how to communicate to others effectively.

But, of course I stopped at the postdoc stage, and therefore did not get much training in the management side of it. In fact, the training of academic researchers often is lacking in that respect — you don’t get much training to become a manager or even as a project leader. So one of the key challenges for me in the first few years was learning skill sets that had never been required in academic research. That means also a lot of knowledge that is brand new in financial management issues, in legal issues, intellectual property management issues — in pure management issues, as well: recruitment, how to select people, what to look for to organize them. All these things are crucial as a manager within a company, but I had never been taught.

I had to learn very quickly within the first few years and I was lucky enough that I had enough people around me among my investors and the shareholders of the company who could give me good guidance and help me learn quickly and correctly.

Can you give an overview of the different projects going on at the company?

The first three years of the company’s growth were really focused inwards, building up the operations and building up the team and building up the tools, the infrastructure, everything. We’ve only come out in public fairly recently — in the last two years, I’d say. So we built up the ability to do genome-based and genome-driven RNAi experimentation in three systems primary: It started off in C. elegans, then we added in Drosophila cells, and then, since 2001, human cells.

Although the largest project initially was the completion of the genome-wide screen in C. elegans looking at cell division genes — that took a lot of effort and allowed us to learn our trade at the beginning — there is not enough demand for our services in C. elegans and therefore that has been phased out. The initial screen has been completed, the work is now submitted and being reviewed for publication, and we’ve finished recently what will probably be our last C. elegans-based project.

We’ve done a few projects in Drosophila cell-based screens. But again there the demand for this type of project is very small, so it is unlikely that we will continue from a service point of view. You may have seen in the press that we announced the release of the Drosophila genome-wide library of double-stranded RNAs with Ambion, so that’s our contribution to that side of industry — to help enable individual labs do that kind of work themselves.

Really the vast majority of what we do now is in human cells — literally almost everything we do is in human cells, and in a variety of different cell lines. Breaking it down: We are doing either target discovery screens, which are usually either in selected subsets of genes, or up to genome scale. In [the] case [of genome-scale projects], the largest right now that’s ongoing is the work with Bayer that was started at the beginning of the year to carry out some target discovery screens over the entire druggable genome, which is between 5,000 … and 6,000 genes.

That’s been the majority of the work: target discovery screening, but also target validation work. Those [target validation projects] usually [involve] much smaller groups of genes, of course, but more detailed analyses in different cell lines. Those are the two major applications.

As things progress, are there different areas [of RNAi] that Cenix wants to move into to drive growth?

Essentially everything we do right now is focusing on the more advanced applications of RNAi in cultured human cells, and occasionally in mouse and rat cell lines. We have an emphasis on applying high-content analysis methods, so we encourage people wherever possible or appropriate to not limit themselves to low-content, single-parameter readouts, but to be more ambitious and try to apply high-content readouts — microscopy-based readouts, in most cases. So there’s still a lot of growth, a lot of development, and a lot of untouched potential that’s inherent in that.

Beyond that, there’s two ways in which we see growth in the field for us: One is horizontal growth and the other is vertical growth, if you will. Horizontal growth would refer to trying to broaden the range of applicability of high-throughput RNAi-based analysis in cell lines for target discovery and validation to a broader range of disease areas; right now, most of the applications we see are limited technically by which diseases are well-modeled in cell culture, which of these cell systems can be transfected easily with siRNAs. [Horizontal growth requires] being able to overcome those technical limitations to allow us to apply the same type of work to other diseases areas, which so far have been difficult to get into — that would include metabolic diseases, inflammation, CNS.

Some of these things require [going] downstream from cell-based work, namely in vivo work. That’s what I would refer to as vertical development — being able to apply RNAi-based technologies to help advance or accelerate the downstream steps of drug development. Once you’ve discovered your targets and characterized them as much you can in cell-based systems, most in the industry like to move on to whole-animal studies. Being able to carry out RNAi in the whole animal and exploit that is on everyone’s wish list. It’s on our wish list and we look forward to exploring that.

The technology has taken awhile to mature enough to be able to do that in a consistent way and in a well-controlled way, but we like the way it looks right now. Doing systemic, hopefully inducible RNAi, in mice and rats is something we’re very excited about — that will come down the road.

Another area of vertical development for the field will be using RNAi-based screening methodologies to not just gain insights on targets and target functions, but rather to gain insights into the mechanisms of action of compounds themselves. Doing experiments combining a compound in RNAi-treated backgrounds opens up a whole other way of using the technology to advance the characterization of compounds.

These are things that will help broaden the impact of RNAi technology on drug development.

One thing that we’re happy about is that for both of those directions — further improving developing technologies for RNAi in cultured cells, but also technologies for RNAi in vivo — we helped put together a major consortium of German labs. It’s called the SMP RNAi consortium, and [RNAi News] actually mentioned it a few months back (see RNAi News, 5/28/2004). That consortium has got a lot of people excited; it brings together labs in Heidelberg, Munich, Dresden, and Berlin, all of which are leaders in the field. We’ve very excited over the next two/three years to participate with these groups to further develop [RNAi].

Last question. Is Cenix profitable?

We are on track to be profitable this year, which will be the first year of profitability for us. For a small German [company in its] fourth year of operation — fifth year since foundation, but fourth year of operation — we’re pretty happy with that.

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