About Metabolomics
What makes metabolomics such a promising technology?
Metabolomics is the study of the small-molecule metabolite profile of a biological organism, with the metabolome representing the collection of all metabolites. What is so exciting about metabolomics is that the metabolome is the very end product not only of the genetic setup of an organism, but also of the sum of all influences it is exposed to, such as nutrition, environmental factors, or treatments.
Even though genomics has successfully identified associations between the genetic setup and specific diseases, the biologic mechanisms through which gene variations influence disease development and severity are often not fully understood.
Research therefore turned to studying the transcriptome—the total set of RNA transcripts in a given organism. Transcriptomics, or expression profiling, assesses the expression level of RNAs in a cell population and provides information on the relative amounts of RNA. However, RNA levels are not directly proportional to the expression level of the proteins they code for. Also, many transcripts are translated into more than one protein, and many proteins form complexes with other proteins and only function in their presence.
The next step, therefore, was to measure proteins directly—the realm of yet another ‘omics’ platform, i.e., proteomics. However, a specific cell type may produce different proteins at different times and under different conditions. Also, any protein can undergo a wide range of posttranslational modifications.
As a result, genomics, transcriptomics, and proteomics merely indicate the potential cause for a phenotypic response, but they cannot predict what will happen at the next level.
Metabolomics is different in that it provides a functional readout of the physiologic state of an organism as determined by the sum of its genetic blueprint, regulation, protein abundance, and environmental influences. It analyzes large arrays of metabolites, thereby extracting biochemical information that reflects the true functional endpoints of biological events. Also, whereas the human organism consists of some 40,000 genes, 150,000 RNA transcripts, and 1 mio unique proteins, the metabolome consists of some 2,500 molecules only and is therefore better amenable to interpretation.
What is unique about the Biocrates approach?
There are two approaches to metabolomics, i.e., targeted metabolomics and metabolic profiling. While both approaches are complementary, targeted metabolomics, i.e., the identification and quantification of defined sets of structurally known and biochemically annotated metabolites, takes advantage of our detailed understanding of most biochemical pathways. In contrast to regulatory relationships at the transcript level or protein interactions, most enzymatic reactions and their end products are well characterized, allowing any pathologies to be traced back to where they actually originate and targeted remedies to be developed.
One major advantage of targeted metabolomics is that it generally provides quantitative information. These quantitative data—the molar concentrations of the metabolites involved in a pathway—facilitate the immediate understanding of deviations from normal. Interpretation of targeted metabolomics data is straightforward, regardless of the cohort investigated, e.g., healthy versus diseased or treated versus untreated. Another advantage of targeted metabolomics is that it is well suited for high-throughput and routine applications.
Proof of concept for targeted metabolomics
Targeted metabolomics was co-pioneered by the one of the founders of Biocrates, Professor Dr Adelbert Roscher, in the mid-1990ies. Roscher and colleagues found that neonatal screening using mass spectrometry enables over 20 monogenic inborn errors of metabolism to be detected. Today, Professor Roscher’s Munich laboratory screens some 1000 newborns daily from dried blood spot samples received from throughout Germany via regular mail. Biocrates was founded based on the premise that the screening successfully carried out in newborns may be extended to the general population.
Advances in mass spectrometry—a prerequisite for metabolomics
The targeted metabolomics approach pursued by Biocrates became possible thanks to significant advances in mass spectrometry. Quantitative tandem mass spectrometry today meets the most stringent quality control criteria for routine diagnostics. As monoparametric biomarkers will increasingly be replaced by multiparametric approaches, the specificity and sensitivity of biomarkers greatly improve. At the same time, mass- spectrometry–based diagnostics will be more cost effective than current approaches—despite offering a wider analytical panel and improved diagnostic quality.
