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Harvard s George Grills Gives His Take on the DNA Sequencing Market

On the heels of last week's announcement that Beckman Coulter would buy Agencourt Bioscience, BioCommerce Week sought opinions from genomic lab customers about the deal and the DNA sequencing instrument and services fields. The following is an interview conducted this week with George Grills, director of DNA sequencing at the Harvard-PartnersGenomeCenter.

How long have you been running the DNA sequencing center there?

The Harvard-PartnersGenomeCenteris part of the Harvard-PartnersCenterfor Genetics and Genomics. The center was established four years ago. So, that's how long we have been doing sequencing at Harvard. We actually moved the genome center, which was established in 1998 at the Albert Einstein College of Medicine in New York City. We started off as part of the Human Genome Project. But before we had a genome center, I had been running a core facility type of operation as well.

How would you describe the demand for DNA sequencing services over the past few years? Is it strong, weak, growing, declining, and/or cyclical?

It depends on the community you're involved with. So, basically I think it's strong and it's growing. The nature is somewhat changing. Obviously, we don't have the public funding for the scale of project like the Human Genome Project any longer, which was quite significant throughput. There are some proposals on the table like the cancer genome project that would have significant throughput as well.

When you look at it, there are the very large genome centers, about a half-dozen in the world, like the Broad [Institute], WashingtonU., and Baylor, which really suck up some large projects. But there is continuing demand for large-scale sequencing projects. What we primarily do here is a combination of whole-microbial-genome assembly type of projects and resequencing projects.

From your experience and knowledge, has there been an increase in pharma and biotech firms outsourcing to DNA sequencing service shops?

A lot of these large-scale pharmaceutical companies have their own sequencing centers. But it's the mid-level and smaller biotech firms and such, which really aren't able to support a full-time infrastructure, that really do need to outsource, and they come to us.

Why do you think there has been a decline in sales of DNA sequencing instruments even as the market for services has remained fairly strong?

It's a good question. It's difficult to narrow and I'm sure ABI has some theories of their own. They reinvented themselves several times. They did a good job of it for each iteration of the technology, and there were impressive jumps in terms of what the technology could do. Starting off with the 373 in the early 90s, you [went] from doing 12 samples and getting 200 or 300 bases in 24 hours, to the 377, which was cutting-edge four or five years ago. There you do 96 samples at a time and you get maybe 500 bases or 600 bases per sample, again which takes about 24 hours. Today, the 3730 can do 96 samples, get about a thousand bases per sample, and do it all in two hours. So, those are substantial leaps in terms of throughput.

There also have been significant improvements in terms of detection technologies, which allows us to use a lot less of expensive reagents. And there's been robustness in terms of the detection software as well as the downstream analysis software packages. So, that's all been tremendous leaps that have fueled demand for the technology.

I imagine that part of the reason they are not getting a huge influx of customers is that all the major genome centers have retooled, so you're not going to get any substantial sales from them now with the current technology. Each of the instruments has such a tremendous throughput that the small-scale facilities have trouble justifying getting them. Rather than these being in individual labs, they're in a core type of infrastructure. So, that means you get more samples going through fewer instruments at each institution.

The real question is what is going to be the next major leap in technology. Depending on what next-generation technology comes to the market first, I think that will definitely fuel a demand for increased sales of the technology.

What is your view of the supposed "quicker and cheaper" DNA sequencing technologies, such as sequencing by synthesis or the single-molecule approach, that are currently in development?  Are you involved with any of the projects developing these newer technologies?

I've been on the grant review panels for the NIH review sessions for responses to applications for both the near-term, $100,000-genome type of technology as well as the revolutionary technology, the $1,000 genome type of technology. The way the NIH has looked at this, which is a very reasonable way, is looking to fund technologies that have the potential of reaching the $100,000 genome in the next five years or so, and reaching the $1,000 genome in the next five to 10 years. Some very clever people have come up with some very clever ways of approaching and solving this problem of doing it faster, cheaper, better.

There already are companies that have released or are about to release some of these technologies - 454 Life Sciences being the first out of the gate - and they've got a very good, interesting technology using pyrosequencing in a nanofabricated format. They've worked very hard on their informatics, which was absolutely required because they're getting short reads. The way they've got their technology now, it's very well geared toward resequencing of bacterial-sized genomes. The Broad has announced that they've already got one of these instruments, and I think it's very appropriate for some types of projects, either resequencing whole microbial genomes or targeted resequencing of other types of DNA projects. They are not quite at the point yet where you could do de novo sequencing of a whole mammalian genome or a whole human genome. That's going to take some solving of technical barriers. I see that as a very promising technology.

Visigen and Solexa also have some interesting approaches for sequencing by synthesis. I think they've got some real promise. Agencourt has been working with George Church [a professor of genetics at HarvardMedicalSchooland director of the LipperCenterfor Computational Genetics] to develop his polony technology, which is extremely promising in my view. It's a very high-throughput way of doing both PCR and sequencing with a very good technology for sequencing as well. I think they're very far along in terms of development. There couldn't be a much better team than George Church's focus on pure research combined with Agencourt's very practical focus on commercial applications for that research. I think they've got a good shot at putting out a technology that will be very useful. They might be one of the first ones out of the gate that might enable us to do whole-human genome sequencing at a significant reduction of price.

How far off do you think some of these new technologies are from reaching the market and replacing the current sequencing technologies and instruments that are already out there?

I have no doubt that one of these [efforts is] definitely going to come out with a commercial product within the next five years. It's easy to say because one already has with 454.

What effect, if any, do you think Beckman's acquisition of Agencourt will have on the sequencing services market? Would you expect other instrument manufacturers to follow Beckman's lead?

It's an interesting strategy and I see some of the logic behind it. We were actually a development site for the application of the Agencourt SPRI [Solid Phase Reversible Immobilization] technology on the Beckman BioMek FX platform. In order to do the types of things you want to do with the Agencourt technology in a high-throughput method, you really have to have a very strong integration with the robotics. So, it's not out of the blue, this relationship.

I can also see that the requirements you're going to have with the commercial application of George Church's polony technology are going to require a significant automation, because when you think about the throughput potential, you're really going to have to handle a significant number of samples in a short amount of time. It makes a lot of sense to have that close-knit cooperation between the development of the sequencing technology and the development of the platform that it's going to be automated on.

As to whether others will follow suit, it's hard to tell. It depends on what technology you're talking about. I'm thinking of the way that both Caliper and Beckman have associated themselves with Affymetrix to develop their high-throughput systems for sample prep.

Do you see genomic sequencing technologies playing a bigger role in drug discovery?

I am not really in the drug discovery field, but, in general, yes I do believe that. One of the focuses of our genome center is translational research, and translating basic research into clinical applications. For example, the personalized medicine type of testing. I can really see a large growth in demand for sequencing in those areas.

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