Measuring the Molecules of Life: Why It Is So Important, and Why We’re Not Very Good at It
Authors:
Thomas O. Metz* ([email protected], PI)
Institutions:
Pacific Northwest National Laboratory
Abstract
Genome-enabled interrogation and manipulation of biological systems is converging with technologies for measuring the phenome and with advanced computational methods for integrating related and disparate data. The scientific community is poised to capitalize on this to explain the bases for health and disease and to harness biological processes for the betterment of mankind and the environment through the toggling of system function.
Molecular components of the phenome include genes, transcripts, proteins, and small molecules, and their measurement is made possible by a spectrum of technologies with broad diversity in efficiency, robustness, and impact. Genomes and transcriptomes are now routinely determined and measured with near completeness using high-throughput sequencing technologies. The measurement of proteomes and metabolomes lags that of their genetic counterparts, although technologies for broadly measuring proteins in high throughput (i.e., proteomics) are much more mature, in large part due to the high correlation of the proteome to the genome. For example, proteins are direct readouts of the genetic code, and if the genome is known, then the proteome can be predicted. While proteins are chemically more complex than genes and transcripts, they are chemically less complex than metabolites. Molecular structures of the latter, having nearly the same chemical composition as proteins, are limited in their complexity only by thermodynamics, and the chemical space is estimated to be 1,060 molecules.
Technologies for the measurement of metabolites, other biomolecules, and anthropogenic compounds have not significantly evolved since the late 1960s, when Linus Pauling implemented the concept of “orthomolecular medicine” to identify biosignatures that were correlated to phenotype. New, paradigm-disrupting technologies and concepts are needed to drive the next revolution in multiple fields of strategic importance to the nation: biological sciences, medical sciences, national security, chemistry, and the bioeconomy. This presentation will critically review the state of the art in measuring molecules integral to the phenome in the context of the respective chemical space and will propose a multidimensional evolution of the analytical approach.
Image
The Molecules of Life. The genome and transcriptome are comprised of DNA and RNA, respectively, which are polymers of four defined nucleotides. Similarly, proteins are polymers composed of 20 defined amino acids. In contrast, the metabolome and related small molecule omes are comprised of molecules with much greater chemical diversity. [Adapted from Metz, T., et al. 2017. "Integrating Ion Mobility Spectrometry Into Mass Spectrometry- Based Exposome Measurements: What Can it Add and How Far Can it Go?" Bioanalysis 9(1), 81–98. DOI:10.4155/bio-2016-0244. © 2017 Future Science Ltd and republished under Creative Commons license (CC BY-NC-ND 4.0)]