NEW YORK (GenomeWeb) – Scientists from AstraZeneca, Waters, and Labcyte have developed a mass spectrometry system capable of running 100,000 samples per day.
AstraZeneca researchers are currently using the system for high-throughput drug candidate screening assays and metabolomic profiling, said Jonathan Wingfield, principal scientist at the drug company and senior author on an Analytical Chemistry paper published this month describing the system.
Wingfield added that the system could also potentially be used for applications like proteomic research.
The platform is currently used only internally at AstraZeneca, but Wingfield said he and his colleagues have been presenting on the system at conferences and through peer-reviewed publications in hopes of gaining wider adoption.
Throughput has traditionally been a challenge for life sciences mass spectrometry, as the upfront chromatographic separation required to go deep into complex samples is a particular issue for certain kinds of experiments like proteomic profiling. For more targeted experiments or experiments looking at relatively high-abundance analytes, researchers can sometimes skip this chromatography step, using direct ionization approaches like MALDI to extract ions from a target sample and direct them into the mass spec without any upfront separation. Such methods allow for high-throughput analyses, with, for instance, MALDI-based approaches letting researchers run a sample in around two seconds.
Rapid injection systems for electrospray ionization mass spec instruments also exist, most notably Agilent's RapidFire, which, according to Wingfield and his co-authors, can inject a sample every five to 10 seconds.
At a rate of three samples per second, however, the AstraZeneca system outstrips even these high-throughput approaches.
The platform is based on acoustic mist ionization, which uses acoustic energy to direct an ionized sample from a plate well into a mass spectrometer. It was inspired by the Labcyte acoustic liquid handling systems AstraZeneca and other labs have used for years as part of their regular research, Wingfield said.
While these devices are useful, they are expensive and not particularly interesting to look at, he noted. "And as with any high-value piece of equipment, when we have people from the board of directors coming around, they want to see where their money is being spent, and these are the sort of instruments they always ask about," Wingfield said.
In order to provide a better visual demonstration of the instruments' value, Wingfield's lab printed and displayed pictures of their internal workings.
"And one of my mass spec colleagues was walking past [the pictures] one day… and he said to me, 'You realize that what you're looking at there is really not that different from electrospray mass spec,'" Wingfield recalled.
This led to the realization that the rapid speed and small sample requirements of acoustic liquid handling systems could potentially enable extremely high-throughput mass spec assays. Wingfield and his colleagues then got in touch with researchers from Labcyte and Waters to see if such a system might be feasible.
"Literally over a weekend," the Waters and Labcyte teams put together a prototype instrument that "generated enough proof-of-concept data to demonstrate that this really had legs," Wingfield said.
From AstraZeneca's perspective, the major benefit was cost savings, as it would allow the company to use mass spec for the sort of high-throughput drug screening assays commonly done using immunoassays.
"When you dig into it and ask what is the major cost associated with running a high-frequency screening campaign, it's the cost of the [antibody and fluorescent labeling] reagents," Wingfield said. He said that AstraZeneca screens potential drug compounds against roughly two million samples.
"If you imagine that each compound costs around $.10 to test, that's $200,000 per target, at 30 targets per year — that's a lot of money," he said.
Using the rapid mass spec platform, the company is able to cut out the roughly $.08 per assay that goes towards reagents. "And it's probably going to give you better data with fewer false positives," Wingfield added. "So for us that was a huge driver."
He said that he and his colleagues have run six full-collection screening experiments using the system and have an additional five that will be completed by the middle of the year.
The researchers are also using the system for high-throughput metabolomic profiling, examining metabolic changes in cells treated with compounds of interest. They have produced early data generating metabolic profiles of liver cells treated with compounds known to cause liver damage that have in some cases helped identify the mechanism by which those compounds cause the damage, Wingfield said.
This work has drawn interest from the academic metabolomics community due to the method's high throughput and small sample requirements, he said. Given the higher complexity of the cell samples, this work requires between two and six seconds per sample, Wingfield said, noting, that this was still much faster than a typical assay.
He suggested the platform might also be useful for proteomics experiments, allowing researchers to rapidly examine larger numbers of fractions from a highly-fractionated sample to identify the fractions containing the proteins they are most interested in, which they could then analyze more deeply with a conventional LC-MS/MS assay. Such an approach would be conceptually similar to the Deep-Dive SRM method developed by researchers at Pacific Northwest National Laboratory.
Wingfield noted that while pharma firms are typically reluctant to discuss their technology development efforts, AstraZeneca has been "very proactive in terms of… going out and speaking about the science and the opportunity that is here."
This is in part due to past experience. "AstraZeneca has a reasonable history of working collaboratively with vendors to produce products that are exclusive to AstraZeneca," Wingfield said. "Our experience is that that usually fails."
"If you really want technology to land and have impact for a significant period of time, you need to make sure it's something that is going to be accepted much more broadly in the industry," he added, noting that this sort of acceptance is necessary to incentivize vendors to support and update an instrument platform.
Asked about potential commercialization plans for the technology, Jeff Tarmy, director of corporate communications at Waters, said the company is "enthusiastic about our research collaborations in place designed to evaluate the technology's scientific potential," and seeks "continued work with our partners to advance AMI-MS is hopes of making it broadly accessible in the future," but said the company was not "currently in a position to discuss commercial access."