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At Toxicogenomics Conference, Proteomics Panelists Discuss Technology Limitations

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Providing further evidence that scientists from diverse disciplines are seeking to apply proteomics techniques to their research, a symposium earlier this month sponsored by the NIH’s National Center for Toxicogenomics featured prominent players from the field of proteomics, including Denis Hochstrasser, a founder of GeneProt, and Emanuel Petricoin, a co-director of the joint NCI-FDA clinical proteomics program.

Through a series of talks and a panel discussion, the proteomics session offered a complementary perspective to the largely genomics-focused conference, entitled “Symposium on Gene Expression and Proteomics in Environmental Health Research”, held Dec. 3-4 at the NIH campus in Bethesda, Md.

In addition to talks from Hochstrasser and Petricoin on their approaches to applying proteomics to therapeutic discovery and diagnostic pattern recognition, respectively, the proteomics session also included a talk by David Goodlett, director of the proteomics laboratory at the Institute for Systems Biology in Seattle, who spoke on chromatographic and mass spectrometry approaches to separating and identifying proteins.

Following the talks, Goodlett, Petricoin, and Hochstrasser, were joined by Carol Giometti, a senior biochemist and 2D gel electrophoresis specialist at Argonne National Laboratory in Argonne, Il. The panel discussion ranged widely, but touched on a number of current issues in proteomics, including challenges associated with identifying proteins with post-translational modifications, and maintaining objective standards for proteomic data.

Addressing the issue of data standards, all the panelists agreed that the current lack of standards presents a severe handicap for researchers attempting to compare data collected using the wide range of proteomics techniques. However, Goodlett suggested that improvements in mass spectrometry software, such as SEQUEST and MASCOT could go a long way towards improving researchers’ confidence in the validity of their results.

In the future, added Petricoin, NCI is planning to develop an “antibody consortium for credentialing” that would serve as a standard-bearer and clearinghouse for validated antibodies for use in protein arrays and other applications. Such a consortium, Petricoin said, could provide an unbiased mechanism for informing scientists which antibodies “seem to work, and which don’t.”

On the subject of protein arrays, Hochstrasser noted that Gavin MacBeath at the Bauer Center for Genomics Research at Harvard University has had success in maintaining the activity of proteins attached to solid substrates with the use of a glycerol medium.

Hochstrasser, who has had some experience working with Ciphergen Biosciences’ SELDI-based protein affinity arrays, said the Ciphergen SELDI technique presents some problems with specificity when comparing samples acquired from different disease tissue. As an example, Hochstrasser noted that mass spectra taken from a patient with myocardial infarction could in some cases be confused with a sample showing merely tissue necrosis.

Hochstrasser added, however, that the Ciphergen chips can also be combined with various mass spectrometry techniques, such as QTOF, and that his group is working to combine the SELDI chip instrumentation with the new MALDI TOF/TOF mass spectrometer. The limitation, he cautioned, is that large proteins do not fly very well in the spectrometer, and digesting proteins from the chips “is not trivial.”

In answering a question about the best technique for detecting proteins with post-translational modifications, both Petricoin and Goodlett agreed that an array-based approach using phospho-specific antibodies may offer a sensitive and quick solution for identifying modified proteins. “Mass spec is good for sequencing, but as an initial step arrays are good,” Goodlett said. Hochstrasser added that FTICR (Fourier transform ion cyclotron resonance) mass spectrometry is the most precise technique for detecting modified proteins.

In summary, Giometti commented that studying the proteome will by necessity require a wide range of techniques. “The proteome is a dynamic entity and we’re going to have to use every one of these tools to get an accurate picture and sift out specific markers that will be useful.”

— JSM

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