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German Team, Fujitsu Build High-Sensitivity Biosensor Chips for Protein Detection

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By Tony Fong

Researchers in Germany in collaboration with Fujitsu Laboratories in Japan have developed a chip-based technology that they claim can detect proteins with greater sensitivity than other platforms currently available.

The technology, which the researchers first described in an article in the Proceedings of the National Academy of Sciences in 2007, is based on a method designed to detect label-free DNA targets. When adapted to detect proteins, it can be 1,000 times more sensitive than a surface plasmon resonance platform, Ulrich Rant, leader of the Nan-Bio group at the Walter Schottky Institute at the Technical University of Munich in Germany, told ProteoMonitor this week.

He and his colleagues are building a prototype platform for the technology and collaborating with hospitals in the Munich area to test it in various disease settings. At the same time, they are forming a company, tentatively named Dynamic Biosensors, to commercialize the technology, which they call switchSense.

They expect to launch the company and with it two products next year: a biochip and an instrument to measure read-outs from the chip.

The technology was developed as part of a partnership between TUM and Fujitsu that began in 2001 and focused on fundamental research of bio-interfaces on solids. It is based on a method that Rant and his colleagues developed a few years ago called switchDNA, in which end-tethered DNA molecules on metal surfaces are "switched," or modulated, by electric fields. The dynamic motions, or swings, of the DNA molecule are then monitored by optical means.

In the current iteration of the technology, protein receptors are attached to the tip of the DNA molecules. By observing changes to the switching dynamics, researchers can determine whether a protein has bound to the surface, since the protein would add mass to the DNA molecule and slow the swing.

More importantly, researchers can infer from these changes certain properties about the protein itself, and eventually identify it.

"By swinging the protein through the liquid, we can infer information about the size and the shape of the protein," and whether it has already bound other proteins or small molecules, or whether it has been modified by an enzyme, Rant said.

The researchers described the switchSense technology in a 2009 proof-of-principle article published in Nano Letters that described how they used it to detect immunoglobulin G antibodies and antibody fragments.

A number of biosensors are currently on the market, including systems from Biacore and QSense. But according to Rant the switchSense technology offers advantages such as the improved sensitivity, which in theory may help researchers particularly interested in detecting low-abundance proteins.

Rant and his colleagues are also working to exploit the technology's size-detection and -analysis capabilities. As an example, in a protein-protein interaction analysis, two 50 kDa proteins would generate the same signal as a 100 kDa protein on an SPR instrument. As a result, the instrument cannot discriminate the 100 kDa biomarker from the two 50 kDa biomarkers.

"In our case, you can [tell the difference] because two molecules [of] 50 kDas will give a different molecular dynamic signal than one molecule with 100 kDas, so you can really discriminate whether this is a congregate of two molecules or whether it's two single molecules at the interface," Rant said. He added that his team is in the process of identifying "proof-of-principle examples now where this is a specific advantage."

He and his colleagues are also keen on leveraging that capability to identify post-translational modifications. "And of course, that would be a very big thing," he said.

At the moment, they are investigating the utility of switchSense for larger PTMs, such as ubiquitination and sumoylation. It is unclear whether the technology would be able to detect smaller PTMs because the change in hydrodynamic radii may be too small and the shape of the molecule would be essentially unchanged, Rant said.

Because switchSense differentiates molecules based on their hydrodynamic shapes, it can also distinguish two molecules with the same mass as long as they have different hydrodynamic radii, he added.

One significant unanswered question about the technology is its specificity, especially as it compares to existing platforms, though the researchers are trying to determine that.

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Rant said that because switchSense is not quantitative, the technology's primary use is for protein discovery and research purposes, though protein concentrations can be determined by methods used for other biosensor platforms, such as by running different flow velocity profiles and seeing how the sensor "reacts to it."

Though the technology may have potential diagnostic applications, in the current state "it's not a diagnostics tool that can really be applied to diseases," he said.

The technology is most useful for targeted protein analysis and not for a large-scale shotgun approach. "The advantage is that you can make a microarray out of this, and then you can glean potentially a large number of proteins, and then do a crude size analysis," according to Rant.

In an e-mail, Kenji Arinaga, a project leader of the TUM business incubation team currently on temporary assignment from Fujitsu, said that the technology may be most valuable for a "quick analysis" of important protein activities "because the activities are related to the size or conformation which we can detect."

Seeding Applications

The technology at the core of switchSense traces its roots to 2001 as part of a collaboration between TUM and Fujitsu focused on fundamental research of bio-interfaces on solids. Arinaga said that the main focus of the original collaboration was to investigate new technology for the detection of binding events with a target protein and to develop "new materials or compounds to capture target proteins instead of antibodies."

Like any commercial entity, Fujitsu is picky about its investments into new technologies, and the company "needs very specific results from [its] investment," he said.

The group within TUM has "always" done its technology development not only from an academic point of view but from an industrial one, he said. The group's "R&D target moved from finding seeds and basic research to proof-of-principle and application-oriented development, which has been attractive to Fujitsu."

Around 2004, Rant said, the collaborators developed their switchDNA method and spent about four years optimizing it. "And then we started to really push it toward applications because we found that it was actually a great mechanism for biosensing," he said.

Along with Rant and Arinaga, the other developers of the technology are Jens Niemax and Ralf Strasser. Together, they are currently forming Dynamic Biosensors to bring the technology to market, and are looking for a fifth partner with financial expertise.

Start-up funds came from the university, Fujitsu, and the German Federal Ministry of Economics and Technology. Rant declined to comment on the funding amount.

It has not been decided what sales and marketing role, if any, will be played by Fujitsu, a Japan-based multinational computer hardware and IT firm.

In addition to expanding the capabilities of the technology, the researchers are building a prototype chip and measurement instrument. Currently, the chips can analyze 24 different proteins in parallel, which would be the throughput when they are commercialized, Rant said.

The chips will be disposable and offered in different versions. One that will have no bio-functionalization will be specifically targeted to academic researchers who want to functionalize the chips themselves. Other chips will be pre-functionalized.

Still to be figured out is how to store and ship the chips. While the DNA layer is "very stable," the type of protein receptors that a researcher may be interested in may not be.

"There's probably going to be two options. One is that a simple protein receptor, like a small molecule that's chemically stable, can be already pre-functionalized, pre-immobilized on the chip and the chip is going to be shipped" as is, Rant said.

But a more complex molecule, such as a protein, will call for a pre-functionalized chip and a protein receptor to be shipped separately. The measurement instrument, also in development, would then perform the final functionalization before the protein measurement is done, he said.