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Nikki Zahl on RNAi at Invitrogen Following the Sequitur Acquisition

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At A Glance

Name: Nikki Zahl

Position: Business segment director of RNAi

Background: Director of cloning and gene expression, Invitrogen — 2000-2003; Various product management/marketing positions, Clontech — 1995-2002; MBA, Santa Clara University — 2000; BA, political science, University of California, San Francisco — 1990

While Nikki Zahl was director of cloning and gene expression at Invitrogen, RNAi was becoming more and more a part of the company’s overall focus. When the company decided the gene-silencing technology deserved its own business segment, Zahl came on to head it up, assuming her current role just about one year ago.

Recently, Zahl spoke with RNAi News about Invitrogen’s RNAi activities now and down the road.

I always ask first off how you became involved with RNA interference.

The two ways in which we became interested in and focused on RNA interference are that Invitrogen has a long history in both transfection and delivery technologies, as well as gene expression. With those being two focuses and core capabilities, of course RNA interference and some of the key foundational papers caught our attention, and we started to do development probably even before I came in early 2002 in some research and development and feasibility programs within the company.

Can you give a little more detail on the evolution of Invitrogen’s RNAi operations?

Sure. I guess just initially there’s been a lot of development as far as testing and understanding the systems — seeing how they worked within the promoters that we already had in expression vectors. The one thing that we learned quite well is that what worked for over-expression does not necessarily work well for a loss-of-function or … RNAi-mediated process.

So actually R&D was spending a lot of time understanding the similarities and differences, and then being able to integrate that with other core knowledge we have, like being able to apply that to delivery technologies, whether it’s lipids or viral. So [the company was working on] better understanding what is common amongst transfection and delivery, and being able to measure cellular changes from an over-expression to an under-expression system.

That is really where we started spending a lot of our time and focus. [Another] area is that we have a lot of experience in oligonucleotide synthesis and chemistry, so there were other efforts within the organization [to develop] our capabilities and quality in being able to not only delivery DNA nucleotides but RNA oligonucleotides.

[We were also focused on] bringing on a strong bioinformatics component — developing an algorithm, going through the internal data we have. As you’re aware, we’ve also acquired an organization: Sequitur. They had seven years of data of all different types of knockdown experiments, either antisense or RNAi. Being able to pool all of that knowledge together on a bioinformatics basis, to really be able to develop good design rules, to be able to design good elements and content, to be able to go in whether it was an oligonucleotide or vector insert for effective loss-of-function, [is key for Invitrogen].

What about Sequitur? Earlier this year, during a conference call, [Invitrogen CEO] Greg Lucier had said that Sequitur would at some point be integrated into the [company’s] Madison site. What’s the timeline on that and how’s the integration proceeding?

The integration of Sequitur has been proceeding really well. They are a very strong team, and have been from the beginning. That was one of the things that really attracted us to the organization: their strong history and the strength of their knowledge and technical capabilities. In addition, they had the foundation of what is Stealth technology. That’s what attracted us to the organization, and we had an acquisition almost a year ago; it happened in the beginning November of 2003.

At this point, we are in the process of transitioning the site, actually to Carlsbad, [Calif.], not Madison, Wis. We have extended relocation to a lot of key individuals, and all of the individuals have accepted the relocation so they’ll be moving to Carlsbad. In addition, a good portion of the organization was actually focusing on different sales roles for Sequitur, and all of the people that were doing that have actually joined into our commercial organization; two of them are remaining in the US, and one person had interest to go abroad and has taken a position in our Australia office.

We’ve been really excited. It’s been a great transition. The team is really good. I won’t say that everybody is relocating; the Boston area is an exciting area, and some people have very strong family or regional ties to the area. Some people have decided to stay, and I’m sure they’ll be able to find really good positions because they’re great. The team has been great, and since us announcing [the move] and working with the team through this, they have remained incredibly engaged.

Long term, I think bringing the whole team together really helps us to mesh and have a good cross-fertilization. In addition, there’s a lot more support here in Carlsbad for that team, as far as career growth and ready access to [resources such as] a bioinformatics team, people who are experts in protein detection, or delivery [experts who can ensure] that our efforts in transfection reagents meet the needs of the RNAi team.

I think long term it’s the best decision. We’re very happy and excited that the core of the team will be staying together. The team altogether is functioning really well, whether it’s across the service organization or the more new-product-development application work organization.

When will the transition be complete?

We’re targeting by the end of the year.

After that’s done, what will Invitrogen’s RNAi operations look like in terms of size, staff-wise?

For RNAi specifically, covering both services, and product and application development, we’ll have approximately 20 to 30 R&D scientists. That’s nobody from a manufacturing point of view, and it’s not talking about … [sponsorship] of research in other groups, whether it’s GIBCO with the cell culture and different cellular expertise, whether it’s Madison with their drug discovery and cell assay development, or Eugene, Oregon.

That’s the core of the RNAi team, but RNAi will sponsor and develop and have researchers in the other R&D groups actually supporting RNAi efforts.

What about sales-wise? What is the team going to look like there?

RNAi is something that is addressed by our full sales team, whether it’s a regular account manager [or a] technical specialist.

With the Sequitur integration almost complete and things really getting going in the sector, how is Invitrogen planning on growing its RNAi operations?

I think I’ll answer that in two primary ways: One, we are committed to staying at the forefront of RNAi and probably gene regulation, to a larger degree. RNAi is a very effective means, but there might be ways to optimize it, there might be a next generation. So a strong commitment to really understanding gene regulation and the best ways to regulate that would be one avenue that we’ll stay committed to.

Another area that I see us working towards is developing integrated workflows for a number of customer segments or applications. To be more descript there, what I mean is that some people will be using RNAi more for a pathways approach: They want to be able to modulate a lot of different nodes on a pathway and develop it into a cell-based assay. … So one thing [we’ll do is develop] integrated workflows that are addressing customer applications.

I guess I should have asked you this right before the last question, but maybe you could give a snapshot of Invtirogen’s RNAi offerings.

Because it’s pretty broad, I think we’ve started to break it down into too many segments, but we have everything from being able to have fully enabled design of every approach for RNAi … whether its synthetic siRNAs or synthetic Stealth RNAi or an shRNA insert that would go into a vector … to the actual content — the content being validated Stealth, siRNA, or [shRNA].

Our next major node would be the delivery. Lipofectamine 2000 continues to be a really great delivery mechanism, especially in a wide variety of cells … and conditions. For more specialized and harder-to-transfect cell systems, or going into primary neuronal cells, [we have] lentiviral and adenoviral [products].

Then the path kind of goes into two different areas. Invitrogen has systems that allow you to validate and verify the level of knowndown. … We have everything to complete that at the mRNA level, [and] we also have Novex gels and different Western products to be able to be validating things at a protein level.

The other node ... is what I think is the heart and core of RNAi. People are trying to do loss-of-function studies to understand what it is these genes or proteins do … so we have, to complete out the RNAi picture, this suite of tools to be able to do that. With Molecular Probes, you have a number of assays, whether it’s cell mobility, apoptosis, or a real cell-based assay to develop a screening mechanism that [allows you to] see that your target is eliciting, maybe, the binding of ligand that you expect, but then specifically knocking out that target to show that the ligand no longer does bind.

What area in that very broad RNAi spectrum do you see as fastest growing?

The fastest growing that I see today is really the validation of reagents. I think that there is also a big uptick in the longer term cell-based assay, so a vector approach. That’s where I see the fastest growth, but I think that’s just where the market is in the sense that first everybody needs to say: Here’s the target I’m interested in, [then] confirm that they’ve got a knockdown before they can really take that next step of understanding function.

I just think that’s where we are.

What about therapeutics? Sequitur had some early work in … the RNAi therapeutics field. Is that something Invitrogen is considering at all?

It is. That’s why we continue to have efforts to make sure that we have the next generation of synthetics. We will always be continuing efforts, [and] we’re in the process of working on a number of collaborations and trying to be testing Stealth’s full ability to be able to go some therapeutic applications. We’re actually in some early … research programs for customers where we’re trying to apply the technology for some of their therapeutic needs.

In addition to that, with our chemistry capabilities, we’re trying to look at what next might really need to happen, whether it’s tissue-specific delivery [or something else]. But, of course, in vivo delivery is what everybody is needing and is probably one of the big goals out there that we’ve been able to effectively do yet.

A side-question: Invitrogen is known for its aggressive acquisition approach. Is that something that we should not be surprised to see … within the RNAi area?

It’s always part of the strategy.

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