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Protein Expression Data Don t Validate Targets, Pharma Rep Tells IBC Meeting

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With sessions on proteomics applications, technology, bioinformatics, business models, protein microarrays, sample prep, and protein-protein interactions, the IBC Proteomics conference in Philadelphia last week covered all the bases. The four-day event, while slightly less well-attended than a year ago, managed to attract a healthy crowd of buyers and sellers eager to network their way to profitability. A few highlights follow.  

Bayer’s Tamburini: Protein Expression Can’t Validate 

Although Paul Tamburini, director of protein bioscience at the Bayer Research Center in West Haven, Conn., described his company’s approach to drug discovery as “primarily chemistry-driven,” his group nevertheless manages to integrate proteomics into several stages of the process, including the validation of targets identified through gene expression, the study of drugs’ mechanism of action, and in the support of biomarker identification. Tamburini, who said he spoke only for the West Haven branch of Bayer’s R&D massif, said his proteomic separations technology is “all off-the-shelf,” and includes 2D gel instrumentation and consumables from Genomic Solutions, Melanie III image analysis software from the Swiss Institute for Bioinformatics, and the ICAT reagent technology from Applied Biosystems. On the mass spectrometry side, Tamburini’s group employs the ABI Voyager DE Pro MALDI-TOF, Micromass electrospray Q-TOF, and Bruker Daltonics’ FT/MS mass spectrometers. “The proteomics platform is not huge, and we’re judicious in how we use it,” he said.

Tamburini also had a few bones to pick with those who talk up the value of protein expression data. “What do changes in protein expression mean?” he asked rhetorically. “It’s second-class data,” he answered, because the observed change in expression cannot be conclusively linked to the cause of the disease. “What matters is the follow-up,” he added. “[Protein expression] data do not validate targets, and never will.”

His group is most interested in using proteomics techniques to study post-translational modifications, Tamburini said, because when misprocessed, the modifications tend to cause serious cellular malfunction. To get this information, Tamburini is looking for array technologies that can provide the necessary capture reagents to isolate modified proteins, and that would ideally be amenable to “interrogation” by mass spectrometry. In the near term, his wish list includes arrays of secreted proteins, drug metabolism enzymes, GPCRs, and nuclear receptors, among others. Tamburini said he is also considering how to adapt his MALDI platform to perform protein profiling experiments, in a manner analogous to Lance Liotta and Emanuel Petricoin’s experiments with the SELDI platform. “We’re also evaluating external development and partnership opportunities,” he said.  

Caprion’s MIPS Avoids Labels, AWAITS Tissue Samples 

In a contrarian approach to measuring relative protein abundance, Joachim Ostermann, director of new technologies at Caprion Pharmaceuticals, described his company’s MIPS (mass intensity profiling system) technique for determining abundance as a function of mass spectral peptide ion intensity. Rather than using a stable isotope label to quantify protein expression, Caprion has developed software for normalizing peptide ion intensity between control and disease protein samples. The technique is compatible with MudPIT, a software package developed by John Yates’ group for identifying proteins by matching peptide mass spectrometry data with protein databases, he said. Caprion’s platform relies primarily on strong cation exchange and reverse phase chromatography for separating proteins, and Micromass Q-TOF mass spectrometers for identifying and quantifying their expression, he added.

As an example of Caprion’s proteomics technology in action, Ostermann described the company’s approach to studying membrane proteins associated with colon cancer. In one experiment using affinity agents bound to magnetic beads, Ostermann said Caprion researchers had identified 432 proteins not detected in an analysis of the unfractionated cell lysate. Of these, 19 percent had never been characterized previously, and 25 percent had been identified in previous studies, but never localized to the cell membrane, he said. Ostermann added that Caprion’s initial studies had involved only cell lines, but the company would begin receiving human colon tissue samples through a collaboration with Carolyn Compton, a professor of pathology at McGill University. In order to stringently characterize the state and grade of the tumor samples, Ostermann said a Caprion employee would be on hand to record “the exact time when the blood flow is cut off from the tumor.” Caprion will receive biopsy samples at a rate of one to four a week, he added. 

Novartis Buys MALDI-TOF/TOF, Develops MOST 

Despite Novartis’ plans to open a new biomedical research facility in Cambridge, Mass., that would include proteomics on its list of research initiatives [see story p. 3], Jan Van Oostrum’s proteomics group in Basel, Switzerland, doesn’t seem to be competing for funds just yet. His group, which falls under the larger umbrella of functional genomics, signed the paperwork two weeks ago to acquire an Applied Biosystems MALDI-TOF/TOF mass spectrometer as a complement to its extensive platform of MALDI-TOF and ABI/MDS Sciex QSTAR instruments. With his new TOF/TOF, Van Oostrum said he has the capacity to identify 20,000 proteins in 48 hours.

To the front end of this mass spec platform, Van Oostrum has added separations of both the gel and non-gel variety, including a reverse-phase and strong cation-exchange chromatography-based separation system, and a new technology called MOST, short for multiparallel off-gel technology. The latter involves a solution-phase isoelectric membrane that Van Oostrum’s group has scaled to a 96- or 384-well plate format. Although the exact specifications of the scheme are unclear, Van Oostrum claimed that the two dimensions of the technique allow for a separation of 0.1 pH, and that the method is amenable to both denaturing and normal conditions. “It’s fast, and we can multiplex by stacking plates on top of each other,” he said.

— JSM

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