Jeffrey S. Buguliskis Ph.D. Technical Editor Genetic Engineering & Biotechnology News
Mass Spectometry Is Positioning Itself to Become A Routine Diagnostic Tool For Physicians And Clinical Researchers
Few other techniques in the laboratory so exquisitely blend the scientific fields of analytical chemistry, physics, and biology better than mass spectrometry (MS). Put simply, MS is designed to identify, and often quantify, the chemical makeup of a sample by measuring the mass-to-charge ratio of the ions that constitute that sample. This technique holds the key advantage of being extraordinarily more sensitive than other methods that are so often used in laboratory medicine. Clinical laboratories are becoming increasingly dependent on MS data within the areas of toxicology, immunology, cancer genetics, and proteomic analysis.
A mass spectrometer can be broken down into three main components. The heart of the device is the ion source—this is where electrons bombard compounds within the sample, creating a mixture of charged particles. The particles are then passed along to the mass analyzer, which uses a magnetic field to progressively focus the ions, allowing them to separate according to their mass and charge. Finally, the individual ions are passed down a narrow tube, at the end of which is a detector that senses the charged particles and displays the results as an ion spectrum.
Modifying any one of these three basic components can dramatically change the output signal for MS machines, and manufacturers are constantly tweaking their devices to suit the diverse needs of researchers looking to take advantage of varying sample inputs with increased signal output.
To Whom It May Concern
MS is an adaptable technique, but it has disadvantages that the industry is constantly attempting to address, especially as the method is increasingly becoming an integral part of clinical diagnostic medicine.
“A major concern in the adoption of clinical mass spec is the added sample preparation and liquid handling required with biospecimen processing,” explains Scott Kuzdzal, Ph.D., general manager of marketing at Shimadzu Scientific Instruments. “Traditionally, sample prep, liquid/specimen handling, and LC-MS/MS acquisition have all been performed on disparate platforms that require different software.” Dr. Kuzdzal adds that newly designed automated platforms “integrate sample/reagent liquid handling, mixing, shaking, heating, and filtration,” which allows for a much streamlined process.
Interestingly, technical issues with MS devices are not the only growing pains that companies face as they shuttle this technology into clinical laboratories. Mass spec machines have been notoriously complex to operate, and there are too few technicians who are qualified to run the equipment, as well as interpret the results.
“Mass spec today remains an expert method, and with little training offered for mass spec in medical technologist programs, most clinical labs are on their own to cultivate the appropriate expertise that will allow them to develop and run the methods they need,” remarks Tamara Smith, clinical global market manager at SCIEX. “This currently limits the technology to laboratories that have the ability to train and dedicate their staff to this technology, not to mention the amount of time that it takes to develop and validate a homebrew assay within the laboratory.”
Bert Top, Ph.D., senior marketing manager of clinical diagnostics at BioMeriuex, was in agreement adding, “Mass spec is a very powerful technology, but in general quite complex requiring highly sophisticated equipment as well as mass spec experts to analyze the data and build the relevant databases for routine use.”
Additionally, the massive glut of data that is generated by MS analysis—similar to what has been a growing problem for users of next-generation sequencing—is beginning to cause frustration among clinical researchers and is a problem that has caught the eye of some MS manufacturers.
“Another major concern associated with clinical mass spectrometry is that LC/MS instruments typically generate an overwhelming amount of data,” Dr. Kuzdzal states. “While great advances have been made in liquid handling and LC/MS acquisition, data review by technicians or lab directors remains a cumbersome bottleneck.” This is an area where Dr. Kuzdzal noted that Shimadzu has taken strides to work with key software organizations like Indigo BioAutomation to increase production through automated data review and maximize the clinical sample workload.
The Reception Perception
Amidst researchers’ concerns about sample prep and data acquisition, clinical mass spectrometry continues to be an expanding area of laboratory medicine. The reception of new MS technology and equipment has been “very positive,” according to Paul Kearney, Ph.D., president and CSO of Integrated Diagnostics. “Our experience is that both the regulatory community and the clinical community are most concerned with the basics: How reproducible is the test? What is your quality record? What is the clinical sensitivity and specificity?”
Bradley Hart, strategic director of life sciences mass spec and clinical research at ThermoFisher Scientific, agrees, adding that “our customers are seeing a number of benefits from using mass spectrometry instrumentation in a clinical setting. We are reducing both the experience and time required to run highly specific mass-spec-based tests, ultimately increasing the number of tests that can be run in a day.”
It has been said that vendors created the need for sensitive MS equipment to be part of the clinical space through aggressive marketing and creative advertising, although many of the manufacturers tell a different tale.
“Clinical laboratories have driven the acceptance of mass spec in the clinical space—this adoption was a pull from clinical labs rather than a push from mass spec vendors,” says Smith. “The adoption was driven by the needs for accuracy and avoidance of interferences, inherent in traditional methods. As comfort with mass spec as a diagnostic technology has increased so has the number of different methods customers have developed for mass spec.”
Advancements and Innovations
While MS is utilized in all corners of modern biology, there have been several areas where clinical mass spec use has gained traction. Clinical laboratories often use MS technology for disease screening and diagnosis, toxicity studies, and in the identification of new biomarkers. However, in recent years, alternatives to standard immunoassay driven methods have been on the rise as MS platforms often make screens much more accurate due to the limitations of nonspecific binding by standard methods.
Moreover, the extreme sensitivity of MS is being exploited for the detection and quantitative measurement of cancer tissue biomarkers. Mass spec methods for the diagnosis of specific disease states like cancer have clear advantages over traditional immunohistochemistry assays. Not only is mass spec faster and more sensitive, but it also has the capacity to employ multiplexing conditions—monitoring multiple analytes at once—and in the case for cancer, screening for dozens of protein and nucleic acid biomarkers simultaneously.
“Multiplexing is an advantage not only from the ability to test many analytes quickly and accurately but because it is performed with a single sample preparation, additional interrogations of the same sample can be performed at minimal additional cost,” Smith says.
“In the next few years we will see more highly multiplexed mass spectrometry platforms with much greater ease of use and integrated sample/reagent liquid handling,” Dr. Kuzdzal added.
Clinical researchers and vendors alike feel that the sky is the limit when it comes to the future of MS for laboratory medicine. Aside from standard regulatory concerns, price seems to be one of the few limiting factors for clinical mass spec.
“Obviously, the start-up cost of implementing an LC/MS test requires a business decision based on a profit assessment,” explains Christopher Gilles, LC/MS product manager Shimadzu Scientific Instruments. “The cost per test must be factored in with the number of expected samples and combined with the capital equipment expense and labor costs to determine feasibility. Only when there are profitable outcomes to the laboratory will an LCMS test replace an already-established test if that test has regulatory approval.”
Yet, clinical MS manufacturers aren’t being hindered by some of the concerns coming from the end users. To their credit, companies are not only trying to tackle as many current issues as possible, they are simultaneously pushing the frontiers of laboratory medicine forward by addressing what they believe will be future needs of their clients.
“The next few years will be critical to continue to improve the database coverage and accuracy,” remarks Dr. Top. “There is also an opportunity to develop the database to identify highly complex organisms.”
“We realize results from clinical and translational protein data are rapidly transforming the future of healthcare by enabling accurate and affordable diagnosis and prognosis, targeted treatments, and monitoring solutions,” Hart noted. “We are committed to providing more reliable and easy-to-use tools to help meet the demanding needs of clinical researchers and core laboratories.”
Smith agreed, noting that customers she has spoken with “have pressed for improvements in the ease-of-use of the user interface, the walk away times for instrument, and the speed to which they can get their first assays into production on the instrument.”
With emerging technologies and increased use, we can expect to see even broader applications of clinical mass spectrometry. In the burgeoning era of precision medicine, MS seems well positioned to provide the heavy lifting for new clinical applications and even replace some of the current routine diagnostic tools.
This article was originally published in the January 2016 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this digital publication, go to www.clinicalomics.com.
Note: This article's headline has been corrected.