This timeline highlights some of the conceptual and technological advancements that have permitted the field of metabolomics to evolve into what it is today.


Untargeted metabolomics reveals key endogenous metabolite associated with chronic pain
Metabolomics implicates altered sphingolipids in chronic pain of neuropathic origin by Patti G.J., Yanes O.,et al.- Nature Chemical Biology
Glycogen metabolism induced by metabolic adaptation to hypoxia promotes optimal glucose utilization in cancer
Glucose Utilization via Glycogen Phosphorylase Sustains Proliferation and Prevents Premature Senescence in Cancer Cells by Favaro E., Bensaad K.,et al.- Cell Metabolism
Global Isotope Metabolomics for Network-Wide Metabolic Pathway Elucidation
Darren J. Creek, Achuthanunni Chokkathukalam, Andris Jankevics, Karl E. V. Burgess, Rainer Breitling, and Michael P. Barrett. Global Isotope Metabolomics for Network-Wide Metabolic Pathway Elucidation Anal. Chem. 2012, 84, 8442-8447


Connection between Gut microflora metabolism shown to contribute to cardiovascular disease
Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease by Wang Z., Klipfell E., Bennett B.J., Koeth R., Levison B.S., et.al. - Nature
Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk by Wang Q., Zhang Y., Yang C.,et al.- The New England Journal of Medicine


metaXCMS meta-metabolomics analysis approach
metaXCMS: A major challenge in interpreting metabolomics data is distinguishing metabolites that are causally associated with the phenotype of interest from those that are unrelated but altered in downstream pathways as an effect. To facillitate the distinction a second-order("meta") analysis of untargeted metabolomics data from multiple sample groups representing different models of the same phenotype was developed - Analytical Chemistry
Central Carbon Metabolism largely regulated by protein lysine acetylation
Regulation of Cellular Metabolism by Protein Lysine Acetylation by Zhao S., Xu W., Jiang W., Yu W.,et al.- Science
Acetylation of Metabolic Enzymes Coordinates Carbon Source Utilization and Metabolic Flux by Qijun Wang Q., Zhang Y., Yang C.,et al.- Science


HMDB: the Human Metabolome Database
HMDB: web-based metabolite data repository.


XCMS bioinformatics platform for untargeted metabolomics
A bioinformatic platform XCMS was developed for untargeted mass spectrometry based metabolomics. XCMS facilitates comparative analysis by allowing for peak picking, nonlinear retention time alignment using endogenous metabolites as internal standards, statistical analysis of the observed metabolites and searching the METLIN database for metabolite idnetification
MZmine introduced
MZmine: toolbox for processing and visualization of mass spectrometry based molecular profile data.


1st meeting of the Metabolomics Society
1st meeting of the Metabolomics Society in Tsuruoka, Japan.


METLIN metabolite and tandem mass spectrometry database
METLIN, a freely accessible web-based data repository was launched to facilitate metabolite identification on the basis of accurate mass and tandem mass spectrometry (MS/MS) data.


Shotgun Lipidomics
Global analyses of cellular lipidomes directly from crude extracts of biological samples by ESI mass spectrometry: a bridge to lipidomics


First use of the word "metabolome"
SG Oliver, MK Winson, DB Kell and F Baganz use the term 'Metabolome' for the first time, published in Trends in Biotechnology.


Untargeted LC/MS metabolomics
Untargeted liquid chromatography electrospray mass spectrometry metabolomics study. Chemical Characterization of a Family of Brain Lipids That Induce Sleep was published in Science in 1995


Hydrophilic-interaction chromatography for the separation of peptides, nucleic acids and other polar compounds by Alpert AJ, JChromatogr., 1990 Jan 19, 499, 177-196
Development of Clinical Tandem Mass Spectrometry
The origins of the widespread use of mass spectrometry in clinical chemistry began with a description of tandem mass spectrometry for neonate screening of inborn errors of metabolism. Millington DS, Kodo N, Norwood DL, Roe CR, Tandem Mass Spectrometry: A New Method for Acylcarnitine Profiling with Potential for Neonatal Screening for Inborn Errors of Metabolism J. Inher. Metab. Dis., 1990, 13, 321-324


NMR based metabolomics
Observation of tissue metabolites using 31P nuclear magnetic resonance. Hoult DI, Busby SJ, Gadian DG, Radda GK, Richards RE, Seeley PJ. Nature. 1974 Nov 22;252(5481):285-7


Human Metabolite Mass Spectrometry Profiling: Mamer and Horning perform extend original 1966 mass-based metabolomics experiments
Mamer OA, Crawhall JC, Tjoa SS The Identification of Urinary Organic Acids by Coupled Gas Chromatography Mass Spectrometry Clin. Chim. Acta, 1971, 32, 171-184
Horning EC and MG Metabolic Profiles: Gas-Phase Methods for Analysis of Metabolites Clinical Chemistry, 1971, 17(8), 802-809
Daum RS, Lamm PH, Mamer OA, Scriver CR A 'New' Disorder of Isoleucine Catabolism Lancet, 1971, 1289-1290
Daum CR, Scriver OA, Mamer E, Delvin P, Lamm P, Goldman H An Inherited Disorder of Isoleucine Catabolism Causing Accumulation of 2-Methyl-acetoacetate and 2-Methyl-3-hydrobutyrate and Intermittent Metabolic Acidosis Pediat. Res., 1973, 7, 149-160
Gibbs BF, Itiaba K, Crawhall JC, Mamer OA A Rapid Gas Chromatographic Method for the Quantitation of Volatile Fatty Acids in Urine J. Chromatog., 1973, 81, 65-69
Gates SC, Sweeley CC Quantitative Metabolic Profiling Based on Gas Chromatography Clin. Chem., 1978, 24(10), 1663-1673
Gates SC, Dendramis N, Sweeley CC Automated Metabolic Profiling of Organic Acids in Human Urine Clin. Chem., 1978, 24(10), 1674-1679
Vrbanac JJ, Braselton WE Jr., Holland JF, Sweeley CC Automated Qualitative and Quantitative Metabolic Profiling Analyses of Urinary Steroids by a Gas Chromatography-Mass Spectrometry Data System Journal of Chromatography, 1982, 239, 265-276


Mass Spectrometry-Based Metabolomics: A Gas-Liquid-Chromatographic Procedure for Separating a Wide Range of Metabolites occurring in Urine or Tissue Extracts
Dalgliesh C.E., Horning E.C., Horning M.G., Knox K.L., Yarger K. A Gas-Liquid-Chromatographic Procedure for Separating a Wide Range of Metabolites occurring in Urine or Tissue Extracts Biochemical Journal. 1966, 101, 792


Argininosuccinic Aciduria
Argininosuccinic acid identified as metabolite upregulated in children. Ultimately the inborn error of metabolism is due to the enzyme, arginino succinase, being missing or damaged in the Urea Cycle. 1960 Biochemical Journal


First described in 1958 Allan et al. in Lancet, and associated with amino acid metabolism. Ultimately the disease is associated with the disregulation of the arginase enzyme resulting in elevated levels of arginine and citrulline


Metabolic patterns in human health
Williams, R.J., et al., Biochemical Institute Studies IV. Individual metabolic patterns and human disease: An exploratory study utilizing predominantly paper chromatographic methods. U. Texas Publication No. 5109, Univ. of Texas, Austin, 1951,204pp [Ed. note: Readers may be interested in a fuller account of these studies: Williams, R.J., Biochemical Individuality, The Basis for the Genetotrophic Concept, Univ. of Texas Press, Austin, 1956 (paperback)].
First report of PTM, subsequently determined to be a driver of Central Carbon Metabolism
Conversion of Phosphorylase-B to Phosphorylase-A in muscle extracts by Fischer E.H., Krebs E.G.- Journal of Biological Chemistry


NMR introduced
Felix Bloch at Stanford University and Edward Purcell at Harvard University simultaneously publish the first NMR spectra in the same issue of Physical Review.


First description of "antimetabolite"
"Production of thiamine deficiency disease by the feeding of a pyridine analogue of thiamine" by DW Woolley and AGC White - July 1, 1943 The Journal of Biological Chemistry, 149, 285-289
Book by D.W. Wooley, A Study of Antimetabolites, 1952 (Wiley, New York) and later a paper "Anti-metabolites" Science 1959


Krebs cycle
The Krebs Cycle - Hans Adolf Krebs postulated the citric acid cycle (also known as the tricarboxylic acid cycle(TCA cycle), the Krebs cycle, or the Szent-Györgyl-Krebs cycle). This work and that which preceded Kreb's work provided an understanding to the big picture of cellular respiration... a series of enzyme-catalysed chemical reactions.


Urea cycle (aka ornithine cycle)
The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions occurring in many animals that produces urea ((NH2)2CO) from ammonia (NH3). This cycle was the first metabolic cycle discovered (Hans Krebs and Kurt Henseleit, 1932). In mammals, the urea cycle takes place primarily in the liver, and to a lesser extent in the kidney.


First mass spectrometer
J.J. Thomson at the University of Cambridge constructs the first mass spectrometer (then called a parabola spectrograph).
Measurements developed for urea, ammonia, creatine, creatinine, and uric acid in urine
Otto Knut Olof Folin report methods for the analysis of urine for urea, ammonia, creatine, creatinine, and uric acid, the major non-protein nitrogen-containing compounds in urine. All works were published in the American Journal of Physiology.


Sugar identified in diabetic urine
Matthew Dobson evaluates urine from diabetics and identifies sugar.


Diabetes measure qualitatively by sweetness
Thomas Willis, an English physician, performs the first qualitative analysis of urine and found that individuals with diabetes mellitus and diabetes insipidus could be distinguished by the sweetness of this biological fluid. This work, entitled Pharmaceutice rationalis, was published in Oxford.


Quantitative basis of metabolism
Santorio Sanctorius, considered to be the founding father of metabolic studies, publishes his work on ‘insensible perspiration’ in De Statica medicina, and determined that the sum total of visible excrement (urine, feces, sweat) was less than the amount of substance ingested. This work is considered the first effort to obtain physiological data and provide a quantitative basis to pathophysiology via meticulous study and precise instrumentation.


Body Fluids used to predict disease
Ancient Greeks recognize the value of examining body fluids (at this time called humors) to predict disease.


Observation and Experimentation approach developed by Galen
Galen creates a system of pathology that combined Hippocrates' humoral theories with the Pythagorean theory that remained unchallenged until the 17th century.