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Getting Serious About Biomarkers

By Mark D. Uehling

May 12, 2005 | In theory, everyone loves biomarkers. In practice, finding reproducible results from standard technologies is anything but simple. So finding tools for confirming biomarkers remains a white-hot area of research, not only in the vendor community but also in government. The National Cancer Institute has awarded $13.4 million to find tools to speed the discovery of cancer biomarkers in the mouse.

Gregory Downing, a health science policy advisor in the office of the director at the NIH, says there is an admission in the scientific community that, for all the promise of biomarkers, hard and reproducible indicators of disease have proven elusive. “There have been mixed successes and failures,” says Downing. “The issue has been the reliability of measurements from instrument to instrument.”

Downing says candidly that the current research is into basic reagents and other software-based tools that should have been developed before all the hoopla about biomarkers. The goal: to ensure that comparisons from one experiment, lab or animal model can be applied reliably to another. “We’re going back,” he admits. “It’s not fun research from a discovery standpoint, but it is developing reagents and specimens for investigators to do cross-analyses.”

Data can be a problem, both to analyze and store. “One of the problems is how you express the data. You can generate terabytes of data over the course of the year,” says Downing. “Our hope would be to develop a common format to download the data. There are several groups that are working on the informatics for primarily mass spectrometry data. This project has the potential to unify a number of these groups,” he adds, citing prominent bioinformatics and proteomics organizations.

Vendor Offerings
The vendor community, of course, has not been standing still. Applied Biosystems (ABI) recently announced that Norwegian scientists have discovered 54 genes with the greatest prognostic value for breast cancer. The company also has several new mass spectrometry-based systems under the BIOiTRAQ brand. Tony Hunt, ABI’s director of proteomics, says that the company wanted one solution to profile, identify and quantitate biomarkers across dozens of patients. “The advantage of BIOiTRAQ,” he says, “is that you get broad protein coverage.”

The system can handle four samples at once, and is a one-step, one-pot process. “For tagging chemistries to be broadly adopted, you need something simple and easy to use and that gets you the quantitative and identification information in one experiment,” says Hunt. “What you can do now is, in a single experiment, find what proteins are changing, get the identification of those proteins, and get lots of absolute quantitative information for those proteins. It moves the researcher into validation very fast.”

Citing an early tester of the technology, Hunt notes that getting a list of interesting proteins could take the scientist a month using a SELDI approach. With BIOiTRAQ, it took a week to find 50-75 promising proteins that could be screened further.

ABI is hardly the only company with full-featured technology that couples instruments and analytical software to find biomarkers. At Waters, the company’s new end-to-end Protein Expression System gives scientists the ability to quantitatively assess changes in protein expression while performing enhanced qualitative protein identification in a single LC/MS run.

The Waters package includes not only instruments but also chemistry, bioinformatics, methods, technical expertise, hands-on support and training and standard operating procedures-all with an eye to reproducible results. Waters says the system can quantitatively profile protein and peptide components in extremely complex matrices, and without the need for costly isotope labeling.

Services Boomlet Coming?
For some, biomarker discovery is becoming a service business, as Ciphergen pioneered. But now the work is fully entrenched in clinical trials and becoming more routine. In January, the contract research organization PPD bought the rest of SurroMed, in which it had previously invested. PPD’s CEO, Fred Eshelman, said at the time: “We believe the FDA initiative targeting the discovery of biomarkers to improve drug efficacy and safety evaluations will result in accelerated client interest and demand. This acquisition will provide PPD the opportunity to incorporate biomarker services at any point in the development cycle, especially during early patient evaluation in Phase II.”

Services are also part of the plan at Hanover, Germany’s Mosaiques Diagnostics, which is focusing on clinical projects. But the company is clearly proud the sheer speed of its databases and applications, some of which are available via web portals. As the company boasts on its web site: “Coupling of two analysis methods-capillary electrophoresis (CE) and mass spectrometry (MS)-enables fast and reliable determination of more than 1,000 different proteins and peptides in body fluids within 45 minutes. Using this software, analysis and interpretation of the huge data sets generated-one run produces up to 1,500 MS spectra-requires no longer days or even weeks, it takes just a few minutes to generate the results.”  l

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