Director of research and development, gene regulation
At A Glance
Name: Peter Welch
Position: Director of research and development, gene regulation, Invitrogen
Background: Postdoc, biology, University of California, San Diego 1994-1995
PhD, biology, University of California at San Diego 1994
BS, molecular biology, University of Wisconsin, Madison 1988
Peter Welch was named director of research and development for Invitrogen's gene-regulation operations in January this year after holding various positions at the company since 1999. Before that, he worked as a senior scientist and team leader at drug-development firm Immusol.
Recently, he spoke with RNAi News about Invitrogen's take on the RNAi research sector and where he sees the company heading as the gene-silencing technology becomes increasingly commonplace in both academic and industry labs.
In the RNAi research market, there's been a lot of consolidation. Where do you see this market heading next, and what's Invitrogen's plan for gaining an edge over the other big players like Sigma and Fisher?
Probably the first thing that comes to my mind is the use of chemically modified siRNAs. I think they are really starting to gain traction in the market right now. People are starting to realize that the advantages these chemically modified compounds have are significant. Just to list a few: The inactivation of the sense strand really removes one whole set of variables from your experiments, you can remove the possibility of off-target effects right off the bat. Another area where [modified oligos offer a] benefit is that they don't activate any of the interferon stress response pathways. Most standard 21-mers don't, but there are some that do, and some of those are sequence-specific but many of them are not. It's a big question mark in people's heads. [They're asking,] 'Is the phenotype I'm seeing really because of what I think it is or is it the stress response that's being activated someplace?' So chemically modified siRNAs are a way to get around that.
The other thing is we've invested a lot of time into building the bioinformatics in [our siRNA] design algorithm to the point where … we have over a 90-percent success rate, meaning that pretty much everything you design off the algorithm is going to give you 70-percent knockdown or better.
The other thing is that we've applied the Smith-Waterman analysis to the guide strand of the siRNA from position 2 through about 12 of the antisense strand, and that's really where all the specificity lies in the siRNA molecule. A standard Blast algorithm doesn't allow you to eliminate perfect matches to other genes within that little stretch. Instead, you have to apply the Smith-Waterman analysis, which is a recursive algorithm and about a 20-minute process for every siRNA you design. We've gone in and pre-designed duplexes for human, mouse, and rat genes all of them, three targets per gene and put the Smith-Waterman into place, so it's really going to increase your specificity.
I think when it comes to people working with large collections, or even just a one-off siRNA, it's great to have one that's designed with that kind of enhanced specificity in mind.
It's interesting what you said about chemical modifications. On the therapeutics side, most people would say you can't just throw naked siRNA into a person and get a proper effect. But on the research side you don't hear a lot about that. Do you get the impression that going forward chemically modified RNAi oligos are going to be the standard?
Yeah, I do. You're right about the therapeutic angle I think most of those are going to be chemically modified in some form. But I think when the chemically modified molecules came out at first [for research purposes], the prices were a little high. People thought, 'I don't really need this so I'm not going to bother.' Now I think there's no price barrier to using the chemically modified [oligos] so there's no reason not to. That's kind of an angle that people are starting to recognize [they're saying,] 'Oh, I can get a whole collection of chemically modified [siRNAs] for the same price as I can for the naked siRNAs, I might as well because those are then going to be the same molecules I'm going to want to use for target validation in animals and, possibly, therapeutics as well.'
The impression I've been getting from people is that the market for RNAi oligos and reagents and that sort of thing is [becoming saturated] … so finding new market opportunities seems to be key. Dharmacon announced they had signed a drug-discovery deal with Alcon, which I thought was interesting. Is that something Invitrogen's looking at expanding into?
I would say we're always open to any kind of [opportunity]. Invitrogen is not traditionally a therapeutic company, but that doesn't mean we wouldn't want to partner with someone who was.
What are your thoughts on looking beyond just providing oligos and that sort of thing for the [research] market? Where do you see new opportunities?
I don't know if I want to give too much away. I think probably some of the more obvious ones. You mentioned the therapeutic arena, and I think that's probably a no-brainer given the chemical modification technologies we have.
I [also] think there's still a big need for collections and the need to screen druggable collections of genes. I'm actually surprised there is still such a market for that.
When you guys acquired Sequitur, you of course got their Stealth RNAi technology. They also had some therapeutic activities going on. What's happened with that research and data? Is it just sitting there or are there plans to out-license it?
That's a good question. The really successful piece of Sequitur, in addition to the Stealth itself, was their services business. Sequitur is a pretty small outfit, but they had a very good services business, and I think they built themselves a very nice reputation. Fortunately, we've been able to keep that. This maybe ties back to your earlier question about where I see the RNAi field going, and I think customized services [are] still hugely popular. We have a dedicated team of scientists here that … all they really do is customized services for biotechs or pharmas or even academics.
With regard to the databases that Sequitur has, a lot of times when you do these custom service jobs, part of that contract [indicates] that this data is only for [the customer] and you can't use it anywhere else or share it with anyone. So I think a lot of what's in our databases are kind of locked up.