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Genospectra Secures IP for Fluorescent Dyes; Signifies Move to Live-Cell Assays

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Genospectra has secured the rights to intellectual property held by The Scripps Research Institute for state-responsive dyes for live-cell biosensing and monitoring protein-protein interactions, the company said last week.

With the IP acquisition, Genospectra adds another item to its molecular biology toolbox, which the company calls “Parallel Quantitative Biology.” Thus far, this initiative has focused primarily on nucleic-acid based applications, such as the company’s QuantiGene platform for gene-expression profiling in fresh cell lysates.

This latest deal, however, provides Genospectra with the licensing rights to a molecular biology tool that shows great promise for live-cell applications in drug discovery, diagnostics, and biodefense.

The IP covers modified versions of merocyanine dyes developed by Klaus Hahn, formerly of The Scripps Institute. Hahn is currently a professor of pharmacology at the University of North Carolina and a member of Genospectra’s scientific advisory board.

“It’s a class of dyes that was originally used in the 1940’s by Kodak for photographic film, and they’re useful because they can be really bright, … are at long wavelengths, and are capable of undergoing big solvent-dependent changes,” Hahn told Inside Bioassays last week.

Hahn found a way to attach the dyes to specific protein-binding motifs that could be used as molecular probes for specific cellular proteins. The dyes possess state-responsive properties, and thus undergo easily detectable changes in intensity or wavelength when the motifs to which they are attached subsequently bind a protein target.

But the dyes have always found limited use in biology, Hahn explained, because they don’t demonstrate the appropriate state-responsive properties. Even worse, they are highly insoluble. So Hahn and his colleagues tweaked the structure and external chemistry of the dyes so that they would not aggregate in the aqueous environment of the cells, and would undergo changes in response to very specific circumstances associated with protein activity in living cells.

A scientific paper describing the dyes and previewing their use as live-cell biosensors was originally published last year in the Journal of the American Chemical Society. Since then, Hahn and his colleagues modified the dyes in such a way to make the live-cell assays possible, research that was published in the September 2004 issue of Science.

“Now we have some that respond to hydrogen bonding at a very specific point, or others that respond when the dye is bent [as in protein conformational change], and some that respond to solvent polarity,” Hahn said.

“But in terms of getting the dyes into cells, that’s why we’ve partnered with Genospectra,” he added. “You might say that with the current version of the [dyes], that’s the Achilles’ heel. One might have to physically inject them, or use electroporation, but [Genospectra] has a really good method for loading these things into cells.”

That method is one of several that are owned by the company, according to Gary McMaster, Genospectra’s chief scientific officer.

“We’ve put a lot of effort into transfection technologies,” McMaster told Inside Bioassays last week. “We’ve worked with everything from nucleic acids, to plasmids and peptides … and we have multiple systems depending on the cargo that we need to deliver.” Such methods were the crux of a deal forged two months ago between Genospectra and RNAi company Dharmacon. (See Inside Bioassays, 8/3/2004).

“In the case of [Klaus’ dyes], we have a unique system that’s peptide-based, where you can conjugate the cargo of interest to this peptide and deliver it to the cell,” McMaster said. “What’s interesting about it is that it also works extremely well in primary cell cultures, which is really where we want to lead this technology.

“For biotech and pharma, and even academia, the real best phenotypic assays are ones that are performed in primary cells, and not your classical workhorse-type cell lines,” he said.

McMaster also said that the new dyes have the potential to be synergistic with PAC (photoactivated cellular) probes, another of Genospectra’s proprietary technologies. These are probes that possess specific photochemistry that allows them to remain inactive, for instance, while being loaded into cells, and then activated with light at a precise point in time.

“The idea here is really keeping things under wraps,” McMaster said, “because with cell physiology, if you put a peptide into a cell, all hell breaks loose. This way, if the [peptides] are caged, they remain inactive.”

“Cells typically compensate for a peptide before you can even study them, but here you can do precise kinetic studies when you activate those PACs,” Hahn added.

PQB = Systems Biology?

To hear McMaster explain Genospectra’s tools for Parallel Quantitative Biology, it sounds like a synonym for “systems biology,” a popular way of describing the recent trend of analyzing biological activity in parallel at the genetic, molecular, cellular, and tissue level. Regardless, it is a direction in which Genospectra is clearly headed.

“The goal of the company is to be able to make parallel measurements in cells and to conduct dynamic cellular assays,” McMaster said. “So this is really on track with what we want to do here, and we see it as one of the most interesting approaches for attacking high-content screening.

“The toughest part has always been going from a biochemical assay to a cellular screening assay and finding out, most of the time, that what you saw biochemically made a lot of sense, but once you went into a cell … you’ve invested enormous amounts of money only to find that it fails because of real cell biology,” he added.

Genospectra’s primary goal is to develop its technologies into commercial products, like the QuantiGene platform. But McMaster said that the company will also be considering partnerships with other companies along the lines of the Dharmacon agreement. One area he mentioned in particular would be working with companies in the diagnostics field by combining the fluorescent dyes and PAC probes with antibodies.

“We’re going to stay true to the life science market,” he said, “but we’re more than happy to partner with others to makes sure the dyes find the best opportunities.”

— BB

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