Chapter 5—Clinical Applications of Metabolomics

Clinical Screening and Diagnostic Applications of Metabolomics

Although metabolite tests, such as the heel-prick test performed on babies after their birth, and cholesterol screening tests have been in use for decades to detect inborn errors in metabolism or disease risk/presence, the diagnostic potential of metabolomics is far more powerful than just these examples. Recent advances in automation and high-throughput techniques have enabled mass spectrometry to make significant contributions to the disease diagnostics and screening landscape.

Metabolomics can and has identified several novel causes of various chronic diseases with previously uncharacterized etiologies, because it can probe complex biochemistry at both the cellular and organism levels as well as from both the host and environment (including the microbiome). This indicates that metabolites play a critical role in disease development, cellular signaling, and physiological control.

Perhaps the biggest contribution made by metabolomics in disease diagnostics is the growing understanding of cancer as a metabolic disease. Although the Warburg effect¹ has long been recognized as a hallmark of cancer, more recent large-scale metabolomics studies have solidified the presence of aerobic glycolysis and glutaminolysis in essentially all tumors and have additionally linked these metabolic processes² to many known oncogenes and tumor suppressors. Metabolomics has also facilitated the discovery of several oncometabolites, which are endogenous metabolites (such as 2-hydroxyglutarate) that sustain tumor growth and metastasis.

Metabolomics has also been used to identify an association³ between increased serum levels of branched-chain amino acids (which act as insulin analogs) and type 2 diabetes risk. In fact, amino acid levels have been reported to be more predictive of disease onset³ than GWAS studies or other genetic data. Other diseases for which a metabolic link to disease etiology has been reported include Alzheimer’s disease, autism, asthma, and inflammatory bowel disease, among many others. A comprehensive list of diseases and their metabolic associations can be found by searching the Human Metabolome Database.

Metabolomics and Precision Medicine

Although metabolomics has several important applications in clinical diagnostics and screening, the biggest opportunity remains with precision medicine. Metabolomics is the measurement of metabolites or small molecules present within an organism, cell, or tissue. Current high-throughput technologies allow for identification of hundreds to thousands of metabolites at a time within multiple samples at once. This makes it the perfect tool for enabling precision medicine,⁴ which takes into account the individual variability that impacts disease etiology and responses to therapeutics to then create customized treatment plans.

Because metabolomics provides a deep look into the metabolites present in any given sample at any given time, it is particularly powerful for characterizing metabolic anomalies associated with disease, discovering and validating new therapeutic targets and biomarkers, and informing the design of personalized therapeutic approaches for patients based on their own unique metabolic profiles. Another aim of precision-based medicine is to facilitate a prevention-based health system. Because of metabolomics’ ability to deeply characterize gene-environment interactions, scientists expect it⁵ to play a critical role in enabling personalized medicine at large.

Although precision medicine is a relatively recent application area for metabolomics, metabolomics has already enabled several important advances⁶ in precision/personalized medicine, including individualized drug-response monitoring,⁷ the identification of novel biomarkers (i.e., novel drug targets), and metabolic phenotyping of tumors,⁸ which can help guide the development of more efficient, targeted cancer therapeutics. Other advances include the combination of DESI-MS (ie, desorption electrospray ionization mass spectrometry) with electro-incision techniques (such as the iKnife⁹) to facilitate precision surgery. As the surgeon’s knife cuts through tissue, the vaporized tissue is immediately pushed through the DESI-MS, providing real-time information about which tissue is diseased and which is healthy, facilitating more precise surgical procedures and avoiding the unnecessary removal of healthy tissue.

Metabolomics also has the potential to transform the drug development landscape. The current development paradigm, which relies on genetic screening and tests in animal models, sees concerningly high failure rates because only about 10% of diseases have a strong genetic basis⁶ and are instead the result of interactions between genes and the environment. Because it is inherently phenotypic, metabolomics is purpose-built to inform better clinical trials with a higher chance of success. For example, one company used Metabolon’s Global Discovery Panel to develop a more efficacious dosing strategy and redesign their clinical trial to bring a microbiome-based therapeutic that had failed Phase II clinical trials through a successful Phase III trial.

Although clinical metabolomics research is growing, many laboratories don’t have the necessary infrastructure and certifications to perform widespread clinical metabolomics. Metabolon offers two different targeted metabolomics panels for clinical research (the Quantose® Insulin Resistance Targeted Panel and the Quantose® Impaired Glucose Tolerance Targeted Panel) that are offered in Metabolon’s CLIA-certified laboratory. Additionally, all global and targeted panels (including custom panels) offered by Metabolon adhere to ISO 9001 standards to facilitate biomarker discovery, drug development, and other pre-clinical and clinical research across a variety of disease landscapes.

What’s Next for Clinical Applications of Metabolomics?

This chapter has explored some of the current and future clinical applications of metabolomics, including its critical role in bringing precision medicine to the forefront. In the following chapters, we’ll discuss the academic and commercial applications of metabolomics to provide a holistic picture of the scientific discoveries metabolomics enables across disciplines.

References

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