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Admitting Its Limitations, Bio-Rad Contends SELDI Still Valuable for Biomarker Discovery

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In their most extensive public comments about the SELDI platform since Bio-Rad Laboratories acquired it from Ciphergen Biosystems last year, officials from Bio-Rad said that despite its shortcomings, the technology is still a valuable tool in the search for biomarkers.
 
Since purchasing the surface enhanced laser desorption ionization system from Ciphergen last November, Bio-Rad has stayed largely silent about the controversial technology and its plans for it.
 
Last week, the company broke its silence in a conference call with reporters specifically to discuss the future of SELDI, providing an itinerary for what it is doing and will do to help researchers using the technology get better data.
 
Company officials also said they are working on developing a next-generation platform for the system.
 
Bio-Rad “has done a thorough evaluation” of the technology since it was acquired, said Diane McCarthy, manager of the company’s Bio-Marker Research Centers, and “come to an understanding of what its key limitations and key strengths really are.”
 
The strengths, Bio-Rad officials said, center around its ability to discover native proteins and peptides. According to Nelson Cooke, marketing manager for protein direction in the laboratory separations division at Bio-Rad, the chip chromatography component of the system “simplifies and enriches complex biological samples and removes salts and detergents that can cause problems in the mass spectrometer.”
 
Meanwhile, the time-of-flight mass spectrometer provides high sensitivity allowing for the detection of low-abundance proteins.
 
“And finally, the high-throughput capability is necessary to process many samples in order to gain better confidence during biomarker discovery and validation,” a research area that is poised to explode, Cooke said, driven by the need to improve the drug discovery and development process. 
 
The market for mass spectrometry based tools for biomarker discovery, he said, is projected at $400 million this year and growing at an annual rate of almost 20 percent.
 
The SELDI products “really enable protein profiling and biomarker discovery, and are a perfect complement to Bio-Rad’s existing product line,” Cooke said.
 
Bio-Rad officials conceded that the SELDI system requires close attention to the workflow, and that study design, sample preparation, and data analysis plays a crucial role in data results. Researchers also need to address the large dynamic range of fluid samples, especially serum and plasma samples.
 
But that is not an obstacle unique to SELDI, and according to Bio-Rad, the platform offers a key advantage because the SELDI chip provides an extra dimension of separation “while doing so in both [a] high-throughput manner and with high reproducibility,” McCarthy said.
 
The company recommends a three-step separation process beginning with fractionation of the sample upfront with chromatography or enrichment steps to deplete high abundance proteins while enriching for low-abundance proteins. Arrays would be used in the second dimension of separation, with the third dimension performed in the mass spectrometer.
 
“Of course, all of this needs to be coupled with data-analysis methods that are appropriate for the study design and for the type of data that many proteomics techniques, including SELDI, generate, which tends to be high-dimensionality data,” McCarthy said.
 
What the platform is not capable of doing, she said, is identifying individual proteins or allowing for the analysis of post-translational modifications. Both applications call for tandem-MS capability, which the current SELDI system does not have.
 
For the short term, Bio-Rad is focusing on the potential of the platform for biomarker discovery and on providing tools to researchers to “optimize the workflow,” McCarthy said.
 
The company has published an experimental design guideline document to help researchers “optimize their sample selection and … SELDI protocols to achieve the most highly reproducible data and yield ultimately robust biomarkers,” McCarthy said.
 
It also is developing a starter kit for array preparation and collection aspects, and an installation qualification-operational qualification package that will allow customers to calibrate and test their instruments. And Bio-Rad will provide a set of recommendations for data analysis that are appropriate for the high-dimensionality data generated by SELDI.
 

“The strategy is to initially focus on the strengths, providing kits and application guides that will help customers optimize their biomarker workflows and yield more robust biomarkers. And then, we’ll be considering the limitations as we continue to try to improve the technology.”

In the medium term, the company is looking beyond the discovery process to validation, verification, identification, and assay development, and is developing applications suitable for the current SELDI instrument. That includes SELDI-assisted purification and immunoaffinity applications and the development of additional sample preparation kits for common sample types, McCarthy said.
 
“In the long term we’ll be defining performance requirements for the next-generation platform, of course, taking into consideration the limitations of the current system,” she said. The company did not provide details about a possible launch for the next-generation SELDI.
 
“The strategy is to initially focus on the strengths, providing kits and application guides that will help customers optimize their biomarker workflows and yield more robust biomarkers,” McCarthy said. “And then, we’ll be considering the limitations as we continue to try to improve the technology.”
 
Buzz to Banishment
 
During its short history, SELDI has gone from being regarded as potentially groundbreaking in its ability to discover biomarkers to being marginalized as a tool with questionable capabilities.
 
Originally developed by researchers at Baylor University, the SELDI platform created a buzz in 2002 when Lance Liotta and Emanuel Petricoin at George Mason University used it to identify protein biomarkers for ovarian cancer, something that had not been achieved before, Cooke said [See PM 02/18/02].
 
Just two years later, however, that excitement turned to skepticism when researchers at the University of Texas MD Anderson Cancer Center, led by Keith Baggerly, reported that they could not reproduce Liotta and Petricoin’s results.
 
While Baggerly’s criticism was aimed more at Liotta and Petricoin’s research methods and study designs than the SELDI technology, the platform, nonetheless, also took a hit, as reflected in its sales. In court documents dated last September related to a lawsuit filed by Health Discovery against Ciphergen, Ciphergen said that “since its inception, it had sold only about 670 mass spectrometry systems” using the SELDI technology.

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