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Finland’s VTT Develops High-Throughput, Next-Gen Cell Array Platform

TURKU, Finland — Researchers at the Medical Biotechnology division of the VTT Technical Research Centre in Finland have developed a miniaturized next-generation approach to microarray-based cell screening, and are now looking for academic and commercial partners to help out-license the technology, according to the division’s director.
Olli Kallioniemi told BioArray News during an interview here last week that the center has developed the application, called ultra high-throughput screening with cell arrays, to the point where it is regularly being used in many research programs. However, as a publicly funded resource focused squarely on technology development, VTT seeks to partner with external parties to commercialize its technology.
“Obviously, for this technology to expand, it needs to be commercialized,” said Kallioniemi. “You can look at the development cycle of the microarray to see how it was developed. In the past, people had their own microarray printing facility and they made their own microarrays. Now everything is done as standard pre-made microarrays and nobody uses their own printers anymore. That is how I see this developing as well.”
Kallioniemi became widely known in the genomics community in 1992 as one of the first scientists to describe comparative genomic hybridization. From 1996 to 2002, he served as section head at the National Human Genome Research Institute in the US, where he helped to develop tissue array technology.
He became VTT’s director in 2002, and last year was named director of the Institute for Molecular Medicine Finland, or FIMM, a joint research institute of the University of Helsinki, the Hospital District of Helsinki and Uusimaa, and the Finnish National Public Health Institute. FIMM also has a molecular medicine partnership with the European Molecular Biology Laboratory.
While at VTT, Kallioniemi, who has a longstanding interest in oncology, shifted his focus from CGH to developing high-throughput cell screening using arrays. According to Kallioniemi, this work was largely supported initially with funding from the €9 million ($12.7 million), three-year MolTools consortium project, financed by the EU through its sixth framework program.
MolTools concluded last year, leaving VTT with an array platform that it could use in its own studies and make available to other researchers and, potentially, to companies. Kallioniemi said that he and fellow researchers are filing patents on the technology and are currently writing papers covering some of the scientific discoveries made with it.
“It is not only a technology that has been developed and shown to technologically work, but it has also given clear, new insights on cancer development and clear new insights on cell signaling,” he said.
The New Platform
Citing the technology’s nascent status, Kallioniemi declined to discuss the features of VTT’s uHTS cell arrays in great detail, but said that it will allow the manufacture of whole-genome RNA interference screening. 
“The previously available cell arrays are much lower in their throughput,” Kallioniemi said. “I don’t think that anyone has achieved a whole-genome cell array screening to be done in a routine way. Essentially, we are talking about whole-genome experiments in a miniaturized format on a single plate.”

“Essentially, we are talking about whole-genome experiments in a miniaturized format on a single plate.”

Kallioniemi estimated that researchers currently use between 120 and 200 plates to perform whole-genome knockdown screening of genes using RNAi or siRNA molecules. The miniaturization of VTT’s platform would therefore allow researchers to conduct higher-throughput experiments, he said.
Miniaturization comes with other benefits. VTT researchers have been able to tweak existing microarray-imaging and data-analysis tools to work with the new cell array platform.
“When you do experiments at this scale and you want to get a readout from each of these experiments, it has been very difficult to undertake high-resolution imaging,” Kallioniemi said.
“For low-resolution, quick scans, we can use the existing equipment that people use. We can generate in 10 to 15 minutes an image that allows us to do quantitative analysis,” he said. “That has not really been possible. The imaging has been a big bottleneck in all experiments around the cell array.”
Kallioniemi said researchers can use existing microarray imaging techniques with VTT’s cell arrays, but can then shift to high-content imaging of the arrays using an automated microscope scanner to look at the hits from the experiment in great detail.
The “final frontier” for the technology would be to achieve live imaging of each cell on the arrays, though such capabilities are years off for large-scale applications, he said. “As the cells are being exposed to these siRNAs or the RNAis, you could do live imaging of the cells as the perturbation is being carried out, but ultimately, having 40,000 spots on a slide, it’s not possible to image them all at the moment,” Kallioniemi said.
New Applications
Part of the reason VTT’s researchers decided to take on cell arrays as a technology-development project is because Kallioniemi himself felt that there was a demand that needed to be filled.
“Most arrays are DNA and RNA and protein,” he explained. “Cells are the next frontier and, if you have the capabilities, the range of applications is really huge in terms of where they can be utilized.”
The most straightforward of applications for high-throughput, array-based cell screening is simple exploration of cellular functions, Kallioniemi said. Beyond that, researchers can use VTT’s tools to explore pathways and genes that are thought to be essential for disease development and identify possibilities for intervention. Finally, there is a pharmacogenomics dimension to using VTT’s cell arrays.
“In cellular models, we can screen RNAi or knockdown phenotypes that arise from the combination of a drug treatment and a gene inhibition, so you can see which genes, when inhibited, increase efficacy of existing drugs, so we could make drugs work in specific conditions,” said Kallioniemi.
VTT has used the platform “extensively” over the past three years, developing it into a “robust technology that works for multiple cell lines [of] up to 50 different cell types” and generating data.
“People previously just described various versions of the cell array,” he said. “Papers have come out, but nothing happens after, and there are lots of papers like that on cell arrays,” he said. “This is something that has become for us a technology that can be widely utilized. Most of all, it is no longer just a technology project; it is a discovery tool.”
Patent Jungle
According to Harri Siitari, a technology manager at VTT, the center is eager to license out the cell array technology. “VTT’s objective is to develop novel technologies to the point of commercialization,” he told BioArray News here last week. “Cell arrays are a good example of this.”
At the same time, any partner that looks to begin selling the technology as a research tool, akin to the many CGH platforms that have been commercialized over the past years on the back of the scientific breakthroughs of the 1990s, is likely to face the same IP challenges that others have faced in the array space.
“We are prepared to license the technology that we have developed, but it’s going to be a similarly complicated story as it was with microarrays, that then it’s up to the companies to work through the patent jungle of microarrays and various versions of cell arrays,” Kallioniemi said.
“I see us as the early-stage proof-of-principle and demonstration site that can show that this works, has some IP that has made the critical components go forward, and can work with industry to license it out, collaborate, propagate, and so forth,” he said.
In the meantime, VTT is looking into developing a cell array manufacturing resource for academics, perhaps through its membership in FIMM. “We will probably set up a national center and that will grow into something more than just a national center for making the arrays because we have a lot of interest from all over the world,” Kallioniemi said.

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