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Hoping to Find a Market, Yale s Michael Snyder Spins His Protein Chips Out to Protometrix

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When Yale University molecular biologist Michael Snyder unveiled a protein microarray containing 5,800 purified yeast proteins — almost the entire yeast proteome — in a Science paper last September, protein chip watchers stood up and took notice. So it was no surprise that he and his colleagues had already founded a company called Protometrix in May in an attempt to commercialize several technologies from the Snyder lab.

Snyder wasn’t alone in his endeavor. His Yale colleague Sherman Weissman, as well as Michael Sherman, the current acting president, and Jon Soderstrom, a managing director in the Yale office of cooperative research, got together in the spring when Snyder realized his research might have applications outside of academia.

Backed by venture capital “in the millions of dollars,” the fledgling company took root last August in 9,000 square feet of lab space in Guilford, Conn., according to Sherman, who joined the company from Molecular Staging, another company he founded. The operation is small — Protometrix has just 13 employees — but Sherman is in the process of filling a variety of positions, including that of permanent president and CEO, he said.

To produce the proteins attached to the chip, the company has licensed from Yale Snyder’s technique for high-throughput cloning, expression, and purification of proteins. The approach is described in the yeast proteome chip paper published in Science. In those experiments, Snyder relied on recombination cloning, expression in yeast, and a one-step purification of GST-HisX6-fusion proteins. However, Sherman said his team is now working on human proteins that are “made in other systems,” but declined to reveal which ones.

To assay enzyme activity, Protometrix is relying on a platform chip technology that Snyder first described in a November 2000 Nature Genetics paper. Unlike the yeast proteome chip, which used a nickel-coated microscope slide, the chip described in this article uses a miniaturized microtiter plate of disposable silicone elastomer.

The modifications have resulted in a dramatic increase in chip density, Sherman said. In the Nature Genetics paper, Snyder described using the technology to assay 119 yeast kinases for activity on 17 different substrates. The prototype chip had about 150 wells and occupied one-third of a standard microscope slide. With the help of liquid-handling robots, Sherman said, “We are now actually looking at devices that hold as many as 100,000 wells on a microscope slide,” a greater than 200-fold increase in density.

Unlike most companies, which are currently developing antibody arrays for expression profiling purposes, Protometrix wants to put protein chips to a different use: analyzing enzymatic function and mapping protein-molecule interactions. “I think our chips would be extremely powerful pre-clinically for finding targets, by mapping pathways, and also very valuable for drug specificity and improvement studies,” said Snyder.

The microwell arrays will be used to functionally analyze sets of human protein families that are “of broad interest from a biotechnology or pharmaceutical perspective,” such as protein kinases, added Sherman. Though he would not reveal the other families, they most likely include other protein-modifying enzymes, such as phosphatases, proteases or acetylases.

Besides functional studies, the company also wants to use its protein arrays to analyze interactions between proteins and small molecule drugs. As an example, Sherman pointed to Snyder’s use of the yeast proteome chip for identifying several novel calmodulin-binding and phospholipid-binding proteins.

The big question is whether Protometrix is on to something profitable. Cambridge, UK-based Sense Proteomic, a potential competitor, recently launched a protein array containing wild-type and 49 mutant forms of the p53 protein, but some scientists aren’t sure selling protein arrays will make money in the long run.

“There will be demand for it, but I think it’s going to be extremely difficult to turn this into something profitable,” said Gavin MacBeath, who develops protein microarrays at Harvard University and has also started a company called Merrimack Pharmaceuticals. MacBeath added that manufacturing human protein chips and assuring their quality — making sure the proteins are pure, full-length, and have defined concentration and posttranslational modifications — is going to be very expensive.

Sherman said that the company is currently addressing the issue of quality control. "Right now we are refining our ability to offer both products and services, and paying a lot of attention to quality control aspects as the technology is transferred from an academic milieu to an industrial one,” he said.

Snyder added that revenue should more than make up for the costs. “Compared to what companies are willing to pay for DNA arrays,” he said, “I predict they will pay much, much more for protein chips.”

Rather than just selling arrays, Protometrix is also hoping to offer analysis services on custom arrays to pharmaceutical partners, such as testing kinase substrates or inhibitors. By the end of this year, it wants to offer array products and perhaps custom arrays containing certain protein families.

— JK

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