Ciphergen was the first off the starting block in the race to develop biomarker discovery tools, but now, Bruker Daltonics is trying to beat it to the finish line.
Bruker is eager to make inroads in a market that many in proteomics still associate mostly with Ciphergen’s SELDI and ProteinChip technologies — although that conception is changing. “In the last three years we have been seeing more MALDI TOF and electrospray being used by biologists in their labs to look at proteomics for biomarker discovery,” Mark Flocco, business development manager for clinical proteomics and biomarker discovery at Bruker and a former Ciphergen employee, said. “To be honest, this is going to be a huge market as we move ahead — there [are] going to be a lot of dollars invested in profiling and predictive medicine and early diagnosis and toxicology from a protein level, and it’s probably a prudent idea for a company that sells these sorts of measuring tools [like Bruker] to be involved with this.”
There is no doubt that biomarkers are hot, and getting hotter. Ever since Emanuel Petricoin and Lance Liotta of the FDA/NCI clinical proteomics program published their ovarian cancer biomarker study in the Lancet last year — in which they used Ciphergen’s SELDI technology to find protein patterns for malignancy — it seems that hardly a week has gone by without more talk of biomarkers. More recently, in the Aug. 9 issue of the Lancet, Richard Caprioli, director of the mass spectrometry research center at Vanderbilt University Medical Center, published a paper describing biomarker profiling patterns that predict the course of lung cancer.
Last week, Cambridge Health Institute hosted a conference in Philadelphia devoted to biomarkers, and the Sixth International Symposium on Mass Spectrometry in the Life Sciences in San Francisco featured five lectures that focused on biomarker discovery (see story, p. 1).
Last week, Ciphergen announced that it would conduct a 14-city seminar tour in September showing off its biomarker technologies. Bruker plans to do a similar tour in the coming months.
While Ciphergen opened its four biomarker discovery centers in 2000 to train customers on the use of its ProteinChip/SELDI system for biomarkers, and to collaborate on biomarker projects, Bruker — traditionally known to proteomics re-searchers as a mass spec company — introduced its ClinProt biomarker discovery system at ASMS in June.
Bruker’s system is a “direct response” to Ciphergen’s, according to Bruker biomarker manager Flocco, but it uses beads instead of a chip for sample preparation, and adds further automation. ClinProt integrates custom-designed magnetic beads for sample separation that have various binding properties, with a MALDI plate called AnchorChip, a MALDI TOF or TOF/TOF, and a software analysis package — all automated and robotically controlled. The system is still in the last stages of beta testing, but is available for orders now and will be delivered to customers in its final form sometime this month, according to Flocco. “We’re cleaning up some loose ends and making sure we have our t’s crossed and i’s dotted. The robot and software are lagging a little behind but they should be coming out in full product this month,” Flocco said.
Bruker has recently opened biomarker centers in Leipzig, Germany, and Billerica, Mass., to aid in collaborations and training related to ClinProt and biomarker discovery (see PM 7-18-03).
Bruker vs. Ciphergen
Flocco used to work at Ciphergen on its biomarker technology before joining Bruker in March to start up the company’s fledgling program. [Leaving Ciphergen] “was a huge philosophical decision and one that I cannot discuss under the terms of my severance package … but I can tell you that I am extremely delighted to be with Bruker, a very forward-thinking company with extremely effective upper management and strong business ethics,” Flocco said in an e-mail exchange on the topic.
But if Flocco is hoping to make his old employer uneasy about Ciphergen’s hold on the market, he has not yet succeeded. “With the exception of reverse phase [affinity beads], MALDI is an awful detection system for any kind of front-end chromatographic separation — you have to use salt, and MALDI has a difficult time with salt,” said Bill Rich, Ciphergen’s CEO, when asked whether he was worried about ClinProt. “The trick we have with our chip is that the last thing you do is run it under water. [ProteinChip] also has chromatographic affinity, and quantitation. When you put the three together, why would you want to detect with a MALDI plate?” Rich also said that reproducibility is lost when beads are used for sample prep instead of plates. “Our reproducibility comes from the fact that the chips are all homogenous surfaces,” he said.
But Flocco pointed out that several researchers have singled out reproducibility as SELDI’s weak point. Petricoin has said that reproducibility is a major limitation of Ciphergen’s technology (see PM 7-18-03). Flocco insists that ClinProt’s reproducibility is high, and that the beads will be superior to Ciphergen’s ProteinChip in several other ways, in addition to being more highly automated. “One of the things that it offers is a higher capacity compared to the chip. And it’s economical — it will probably cost about $1 to $2 per assay to run,” Flocco said.
Sue Carruthers, executive assistant to Rich, estimated the per-assay cost of running SELDI to be “several hundred dollars.” Flocco also said that SELDI is not so different from MALDI — and thus that the problems with the technologies should be similar. “SELDI is nothing more than MALDI with a capture,” he said. Ciphergen just released a new matrix-free product — surface-enhanced neat desorption — that Rich says will solve the problems of both SELDI and MALDI.
Paul Tempst, director of the protein center at Memorial Sloan-Kettering Cancer Center in New York, has been collaborating with Bruker on biomarker projects, and he uses magnetic beads made by the same vendors that Bruker uses. In a talk at the recent San Francisco mass spec conference, Tempst presented marker patterns he found using the beads and Bruker’s Ultraflex MALDI TOF/TOF instrument. “The beads are good because they are easy to use and automate,” Tempst later told ProteoMonitor. “And we can get them made to different specifications — Ciphergen can’t make five or six plates.”
The most common criticism of Ciphergen’s system is not its chip but its mass spec. “The perception is, we have a bad mass spectrometer,” Rich admitted. “But what we wanted to do was focus on what biologists want. We tell them, ‘You can’t have the highest resolution and the highest sensitivity — which do you want?’ [They say,] ‘I want sensitivity.” Rich said that Ciphergen’s target marketing group — small lab researchers — did not care as much about resolution as large core facilities did. SELDI’s sensitivity is typically in the high attomole to low femtomole range, while its resolution is 50 to 100 on proteins, according to the company. Rich recognizes, however, that this lack of concern with resolution is not universal. “We built a ProteinChip interface, so if you really want to take our chip and put it onto an ABI Q-Star, you can do that,” Rich said. Petricoin recently chose this option for his continuing ovarian cancer studies, citing as a reason that his models “got much, much better” using the Q-Star with a ProteinChip interface (see PM 7-18-03).
Ultimately, Flocco believes that Bruker’s offering will be superior to any option that Ciphergen sells. “It’s not my job to kick Ciphergen out of the market; it’s my job to offer an alternative to what they do in a more efficient manner. We can offer more tools to throw at it than they can,” Flocco said. “If [the customer] wants to go electrospray, [Ciphergen doesn’t] have an answer and we do. If they want to go with FT-MS or ion trap, we have a solution to that. Bruker is a tools manufacturer that very badly wants to get into the biological market, and we have the tools. It’s just a matter of getting name recognition.”
Even if Bruker or others do kick Ciphergen out of the biomarker market, that won’t worry Rich. “Let’s see what an ultra resolution mass spec can do [with biomarkers]. Go for it. While they’re working on that, Ciphergen is turning to target validation,” Rich said.
COMING SOON: ProteoMonitor visits Ciphergen’s headquarters: a feature story