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Abstract and Introduction
Abstract
Genome-wide studies in inflammatory bowel disease (IBD) have allowed us to understand Crohn's disease and ulcerative colitis as forms of related autoinflammatory disorders that arise from a multitude of pathogenic origins. Proteomics and metabolomics are the offspring of genomics that possess unprecedented possibilities to characterize unknown pathogenic pathways. It has been about a decade since proteomics was first applied to IBD, and 5 years for metabolomics. These techniques have yielded novel and potentially important findings, but turning these results into beneficial patient outcomes remains challenging. This review recounts the history and context of clinical IBD developments before and after proteomics and metabolomics IBD in this field, discusses the challenges in consolidating high complexity data with physiological understanding, and provides an outlook on the emerging principles that will help interface the bioanalytical laboratory with IBD prognosis.
Introduction
In 1990, the human genome project was launched by the National Human Genome Research Institute (Maryland, USA) and the US Department of Energy with the mammoth objective of sequencing the entire human genetic code.
The international consortium charged with the task endeavored to make universally available genetic sequences as soon as they were discovered, and these were rapidly mined by scientists in search of a genetic basis for the inflammatory bowel diseases (IBD). Results were immediate, with the first Crohn's disease (CD) gene (IBD1 locus on chromosome 16) being reported by Hugot and colleagues in 1996, quickly followed by successive discoveries of other CD and ulcerative colitis (UC) susceptibility loci.
The human genome contains within it the initial conditions by which disease manifests in the body. However, this information alone is inadequate in elucidating physiological process, of which conceivably millions of distinct molecules (resulting from an unknown number of post-translational modifications [PTMs]) interact at varying levels of selectiveness in time frames that range from milliseconds to years. Indeed, it has been argued that the possession of the human genome has made little effective change in clinical IBD.
Other comprehensive tools in molecular biology soon emerged with the aim of building on our genome knowledge to understand transcription, the resulting protein activity, and elucidate the absolute extents of physiological pathways. Collectively termed "functional genomics," "systems biology," or more colloquially "omics," transcriptomics (an extension of genomics that includes RNA characterization), proteomics (the study of the set of proteins encoded by the genome including its isoforms, modifications, interactions, and structure), and metabolomics (the study of endpoint metabolites) bear a collective ambition of uncovering the complete spectrum of biochemical function.
Prior to "omics," biomedical discovery workflow was a naturally evolving one. Initiated by an exceptional observation, a hypothesis was formed and clinical and scientific experimentation applied to evaluate the theory. Analytical techniques progressed, but this general schematic remained unchanged. Depending on the source of the measurable variable, technologies ranged from liquid chromatography (LC) and gel-based electrophoresis in the bioanalytical lab, to ultrasound, magnetic resonance imaging (MRI), and X-ray in the clinical setting, among others.
What "omics" pledged was the idea that the biological world had definable limits (in spite of its scale). In the course of time, clinicians and scientists would have a complete set of variables to compare states of disease and health without prior hypothesis.
Of the "omics," proteomics and metabolomics are unique in their potential to significantly guide clinical practice in the management of the IBDs. Proteins are the dynamic functional workhorses of physiology, while metabolites are "small molecules that are chemically transformed during metabolism and … provide a functional readout of cellular state."
Just as geneticists began searching for disease genes with each successive completion of chromosome sequence, proteomic and metabolomic scientists immediately began comparing molecule abundance between phenotypes as technological capabilities gradually allowed.
The year 2002 saw the first hypothesis-free "proteomics"-termed publication in IBD, when an international group explored protein changes in intestinal epithelial cells exposed to various cytokines. Four years later, H nuclear magnetic resonance (NMR) spectroscopy was utilized in the first IBD metabolomics publication to examine the fecal metabolome of CD, UC, and healthy controls.
Ten years on, have the hypothesis-free explorations of the IBD proteome and metabolome changed the way we manage these conditions?
Examining proteomics and metabolomics in the context of their applications in the IBDs—conditions that have been studied since and alongside the inception and development of "omics"—is appropriate in illustrating the perils and promise of systems biology science.
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