The NIH has awarded approximately $1.6 million to Burnham Institute researcher and automated imaging pioneer Jeffrey Price to develop a "next-generation" imaging cytometer that may have a 10-fold higher throughput than current comparable systems on the market, CBA News has learned.
Once developed, the platform may help bring information-rich cell-based assays into the realm of high-throughput biochemical screening, which could increase the speed of image-based drug screening and chemical genomics studies such as genome-wide siRNA screening.
The four-year grant began late last year through the National Institutes of Health Molecular Libraries Screening Instrumentation program, which the NIH started in November 2004 to encourage researchers to develop instruments "suitable for integration into large high-throughput screening operations and compatible with scalable approaches to chemical genomics research." (See CBA News, 11/30/2004).
Price, who is an associate professor at the Burnham Institute, as well as an adjunct professor at the University of California, San Diego, invented the EIDAQ 100 imaging cytometer, which he brought to market with start-up Q3DM and eventually licensed to Beckman Coulter, which turned it into the IC 100.
"Some of the instruments [on the market] will go faster by doing binning, decreasing the resolution, and increasing the sensitivity … but the trick there is to ask what the image resolution is, and what kind of information they're getting at their highest rate."
This instrument is still one of the higher throughput automated imagers on the market; however, Beckman recently chose to drop the product line as part of a massive restructuring effort (see CBA News, 11/21/2005).
Price still has a hand in the future of that instrument, as he is part of the original Q3DM trust that owns the associated IP, and, together with Beckman Coulter, is currently shopping the technology (see CBA News, 2/17/2006). In the meantime, Price has been developing the new cytometer.
The platform, which if successful could eclipse the IC 100, is currently called a "continuous-imaging high-throughput screening" tool. It is based on work that Price began in the 1990s around the time he started Q3DM. The instrument contains a set of several high-resolution CCD cameras that continuously scan well plates and, through a feedback loop mechanism, will constantly autofocus with minimal user input.
According to Price, the goal of the current grant is to develop an instrument that is capable of capturing cellular images from approximately 100,000 wells per day a number that has until now been exclusively in the realm of high-throughput biochemical screening. In fact, he said, this type of throughput could be 10 times faster than what is capable with instruments in the IC 100 category.
"Some of the instruments [on the market] will go faster by doing binning, decreasing the resolution, and increasing the sensitivity," he said. "They can definitely move that number up faster. I think Evotec may be going at more like 50,000 wells per day peak, but the trick there is to ask what the image resolution is, and what kind of information they're getting at their highest rate."
Price estimates that microscopes running with medium resolution that is, approximately 0.5 to 2.0 µm with 10X to 20X objectives are usually limited to about 25,000 wells per day. Price proposes to push the new instrument to capture medium- to high-resolution (0.3 to 2.0 µm) images at 10X to 40X magnifications with a much higher throughput.
The upshot of this would be that researchers conducting high-content image-based screens to identify multiple drug targets and effects may be able to do so much earlier in the drug-discovery process.
Of course, an instrument with this type of speed could present a bottleneck in image analysis and informatics. Price and colleagues will not specifically address this challenge using this grant money, but have applied for another grant to investigate some of the informatics challenges.
"At a surface level, the first thing people tend to say is, 'Oh, my God, how am I going to store all that data?'" Price said. "The way I look at it is that hard drives are getting cheaper, bigger, and faster than almost anything else in technology right now. So while storing the data is technologically challenging, I think it's a challenge that will continue to fall away rapidly as the storage becomes cheaper and cheaper over time."
Price sees the real difficulties in analyzing and interpreting quantitative information from a bunch of pictures.
"The main challenge is if you've got images of, say, 200 million cells a day using a technology like this, then how do you go through all of those images and make sense out of all those cells and what they mean?" he said. "How do you pull information out of them, how do you mine them for important information, and how do make that information available to people who want to look at it in different ways? We'll be able to generate a huge amount of information, and the challenge is then making sense of it."
Once completed, the new technology will be in the hands of the Burnham Institute, which will likely seek to outlicense it. But before that happens, Price said, he aims to place the instrument in the Burnham's newly established San Diego Center for Chemical Genomics, one of the nine institutions recently tapped to be part of the NIH's Molecular Libraries Screening Centers Network (see CBA News, 6/20/2005).
"We'll bring this instrument into use in the facility as quickly as possible, and then discuss doing the same with other [labs] that are interested in higher speed instruments," Price said. "I'd like to develop a little user group that has a few instruments running at this speed so we can make sure the instruments can do what they want them to do, and to make sure we put the right features in the instrument from the get go, as we design it."
Ben Butkus ([email protected])