How Mass Spectrometry Is Revolutionizing Precision Medicine

Imagine being able to identify and locate all molecules in a patient at once. We might actually have a shot at preventing or curing almost all diseases. Since we cannot do that yet, we must rely on snapshots using instrumentation. One area of healthcare that benefits from technological advancements is precision medicine. Precision medicine considers a patient’s genetics and epigenetics, including lifestyle and environmental influences, to help select the right treatments or preventive measures for a disease in a personalized manner. Instead of a one-size-fits-all approach, precision medicine recognizes that a personalized approach is necessary for meaningful treatment. Although much of precision medicine is focused on cancer research, a long-term goal is application for all areas of health on a large scale.

The importance of protein biomarkers

Much of the current precision medicine research is focused on the identification of protein biomarkers, which are distinct from genetic markers. As Robert Georgantas III, Senior Vice President of Research and Translational Science at Biodesix, explains, “Protein biomarkers have the advantage that they make up the actual molecular phenotype of disease, as they are at the end of the DNA-to-RNA-to-protein progression from genotype to phenotype. It is important to keep in mind that mutations observed at the DNA level, or expression differences seen at the RNA level, are not always seen at the protein level.” These discrepancies can arise due to epigenetic or RNA-based regulation of gene expression.

One bottleneck in the search for protein biomarkers is quantitation. Many assays quantify one molecule at a time, but sometimes multiple protein biomarkers are involved in a diagnosis. In addition, most protein biomarkers originate from proteins found in high concentrations in serum or tissue, meaning that lowly expressed ones may be missed. That’s where mass spectrometry (MS) can help.

The advantages of using mass spectrometry

Conventional immunological assays include the enzyme-linked immunosorbent assay (ELISA), which is currently used in precision medicine, and the radio immunoassay (RIA). Both suffer from limitations affecting applicability. As John Gebler, Director of BioPharma Market Development at Waters Corporation, puts it, “Even ELISA assays, which can be very sensitive and have reasonable dynamic range, don’t tell one what is being measured. An unpredicted non-specific reaction or interference can lead to erroneous result.” In contrast, MS is relatively reagent-free and cost efficient, and can multiplex analyses in a specific manner.

MS measures the mass of atoms and compounds by first converting the sample into a gas phase, followed by ionization. The ions are rapidly accelerated through an electrical field and sorted according to their mass/charge ratio. The resulting spectrum allows researchers and clinicians to identify the molecular composition of the original sample. The technology has advanced rapidly. Now, mass spectrometers can fit on a benchtop, increasing accessibility for researchers and clinicians, allowing them to analyze numerous protein biomarkers from a single sample in a single test simultaneously.

For example, the Biodesix deepMALDI technique can simultaneously measure over 2,200 whole proteins from serum or plasma. Similarly, SCIEX SWATH acquisition allows for unbiased comprehensive quantitation of all detectable compounds in a sample with a data-independent acquisition method called MS/MS^ALL, which uses electrospray ionization with quadrupole time-of-flight MS. As Aaron Hudson, Vice President of Global Marketing and Strategy at SCIEX, explains, this technology has, “enabled scientists to reproducibly quantify thousands of proteins in hundreds of samples and start to deliver proteomics on the scale of genomics.” On a large scale, the time it takes to diagnose a patient can be dramatically reduced.

MS is sensitive and can detect protein biomarkers in lower abundance, including those with post-translational modifications. The Bruker timsToF instruments, for example, can rapidly assay tens-to-hundreds of thousands of peptides in each sample, making them useful in precision medicine.

Continued improvements in instrumentation and methods in peptide-based proteomics have advanced hypothesis-driven, protein panel approaches, making them stable and robust enough for use in precision medicine. The Biodesix Nodify XL2 assay, for example, uses “multiple reaction monitoring (MRM) mass spec to quantify two protein peptides associated with lung cancer, that in combination with clinical factors, determines the risk of a lung nodule being benign vs malignant,” Georgantas explains. Along with refinements in both select and parallel reaction monitoring, these have allowed assaying of larger protein/peptide panels.

Another breakthrough in liquid chromatography (LC) technology is the application of high-performance surface technologies such as the Waters MaxPeak HPS. Gebler explains, “MaxPeak HPS technology is a hybrid organic/inorganic surface technology that forms a barrier between the sample and the metal surfaces of both the LC and column. By mitigating, or eliminating altogether, non-specific adsorption, it greatly improves robustness, reproducibility, analyte recovery and assay sensitivity, and the accuracy of analyte identification and data interpretation.” With MaxPeak HPS, hours-long system and column passivation isn’t required, freeing up instrumentation for protein biomarker identification.

The increase in accessibility, robustness, methods, and technology has led to discussion about the widescale adaptations of MS to discover or identify treatments for patients in a personalized manner.

The future of mass spectrometry in precision medicine

Medical diagnostics has relied on immunoassays for over 50 years. As MS continues to improve and address some of the limitations of immunoassays, it will play a growing role in precision medicine. Faster turnaround time, increased specificity and sensitivity, and multiplexing are key in rapidly developing treatment plans in a personalized manner. Hudson is excited about the future of MS in precision medicine, especially with the addition of ion mobility and alternative fragmentation techniques such as electron-activated dissociation, which will further increase differentiation and specificity measurements. He states that new and improving technology will, “create a full digital fingerprint of patient samples that will be able to connect phenotype, diagnosis, treatment, and outcome at the molecular level; and innovations in machine learning, data processing, and software will pull the signal from the noise so that physicians can deliver the right treatment for the right person at the right time.”