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Vanderbilt Wins $10M from NCRR to Establish Proteomics Imaging Resource

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By Adam Bonislawski

Vanderbilt University has won a five-year, $10.3 million grant from the National Center for Research Resources to establish an NCCR resource focused on imaging mass spectrometry – a technique that provides cell and tissue localization data on proteins, as well more traditional proteomics information like relative quantitation and analyte IDs.

Work under the grant will concentrate primarily on improving imaging mass spec instruments and workflows and driving specific research into prostate and breast cancer; heart valve development, pancreas development; serotonin signaling; age-related macular degeneration; and kidney disease, Kevin Schey, professor of biochemistry and ophthalmology and director of Vanderbilt's Vision Research Center proteomics core facility, told ProteoMonitor.

A portion of the funding will also go toward the purchase of a new MALDI TOF-TOF MS-MS machine from upstart mass spec firm Virgin Instruments, Schey said.

Virgin Instruments was founded in 2005 by Marvin Vestal – the former president of mass spectrometry platform R&D at Applied Biosystems and developer of the first commercial MALDI-TOF mass spec – and is focused on building a new line of MALDI-TOF instruments for a variety of applications including imaging mass spec.

According to Vestal, the company has been collaborating for several years on imaging mass spec systems with Richard Caprioli, director of Vanderbilt's Mass Spectrometry Research Center and head of the NCCR-funded program. Caprioli's team has used two earlier Virgin prototypes for recently published imaging mass spec work, Vestal said, and will add the new MALDI TOF-TOF MS-MS instrument this year.

More than a straight commercial sale, the arrangement calls for Vanderbilt to "pay the basic cost of [the machine], and then we'll collaborate on refining it," he told ProteoMonitor.

"We're purchasing the instrument, but [the award] is also to help develop the instrument," Schey said. "You could think of it as sort of a beta version coming to our lab, and then we'll give them feedback to help improve the product."

The MALDI TOF-TOF MS-MS machine is one of several MALDI-TOF instruments Virgin plans to launch for sale in early 2012.

"We've got a whole line of MALDI-TOF instruments, ranging from a simple linear instrument that's used mainly for the high mass stuff like proteins and oligonucleotides to a very high-resolution instrument for getting accurate masses on peptides and lipids and so forth, and then the combined TOF-TOF, which does both high-resolution MS and MS-MS at very high speed," Vestal said, noting that collaborations with beta testers like the new Vanderbilt NCCR resource will help set the stage for the coming roll-out.

"We've been doing prototypes working with people like Caprioli, and now we're at the point where we plan to start manufacturing these in the next couple of months," he said. "We'll do a little more collaboration with beta test sites just to finish up all the details, and we're hoping to be in production early next year."

While imaging mass spectrometry is typically done on conventional MALDI instruments, it requires specialized imaging software. According to Schey, Bruker, which offered the first integrated MALDI imaging platform with the release of its flexImaging software in 2005, has traditionally been the dominant player in the field. Recently, though, he noted, companies including Waters and Applied Biosystems have introduced imaging software for the technique.

With the NCCR award, the Vanderbilt researchers aim to improve the spatial resolution and sensitivity of existing imaging systems, Schey said. Currently, spatial resolution tops out at 5 to 10 microns for lipids and 20 to 40 microns for proteins. The goal, he said, is to bring it down to 1 to 5 microns for both.

Also important is upping the speed of imaging mass spec systems, Vestal said, noting that this was among the main contributions of the prototype Virgin was selling to the university.

"If it takes you 24 hours to produce a small image, that's interesting from a scientific point of view, but it's not very useful from a practical standpoint," he said. "So what we're working on are faster systems that can do this in minutes instead of hours."

Key to this, he said, is increasing the frequency of the laser used in the device. According to Vestal, Virgin's new machine operates at 5 kHz compared to around 200 Hz for current commercial instruments.

Sample prep has also been a traditional stumbling block, Schey noted. In particular, researchers have had trouble evenly coating tissues with the matrices used in MALDI mass spec. Uneven coating leads to uneven signal, which can cause variability within and between samples. In collaboration with liquid handling firm LabCyte, Vanderbilt scientists have developed a robotic spotting method that significantly reduces this problem, Schey said, and part of the grant will be used to further improve that technique.

In addition to the Virgin and LabCyte work, the award will also fund collaborations between the NCCR resource and scientists doing basic biological and clinical research. Schey cited cancer diagnosis as "a classic example" of a potential application for the technology.

"Typically cancer cells are identified by a pathologist who just looks through a microscope at a stained tissue and says, 'These cells look cancerous and these don't,'" he said. "But there's no molecular information there whatsoever. If we could take that same biopsy and image it for the molecules present we would say, 'These molecules are present in cancer cells and these are present in normal cells,' and you can much better define where the tumor margins are. That's one example of where the spatial information and the molecular information are really important."

Another, Schey noted, is in the study of development. For example, "the molecular events when heart valves are developing are simply unknown," he said. "So tissue engineers want to know what are the molecular signals that are changing as the valves are developing so they can engineer a valve de novo. And the spatial orientation of the cells and the signals that are produced is critical."

Despite its potential applications, imaging mass spec is still an emerging technology and largely the domain of specialists. The NCRR grant calls for the Vanderbilt center to increase use of the method via workshops and visiting scientist programs.

The "thinking is that this approach will be really beneficial in terms of diagnosing disease and understanding the disease process," Schey said. "Part of the goal of the grant is to make the technology more amenable and more accessible to the mass spectrometry community. If we can achieve that, more people will want to use it."


Have topics you'd like to see covered in ProteoMonitor? Contact the editor at abonislawski [at] genomeweb [.] com.

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