The Human Metabolome Project: Its Application to Disease Diagnosis  Monitoring

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The Human Metabolome Project: Its Application to Disease Diagnosis Monitoring

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1. The Human Metabolome Project: Its Application to Disease Diagnosis & Monitoring David Wishart University of Alberta [email protected]

2. The Pyramid of Life

3. Why Are Metabolites Relevant?

4. Human Metabolome Project $7.5 million Genome Canada Project launched in Jan. 2005 Mandate to quantify (normal and abnormal ranges) and identify all metabolites in urine, CSF, plasma and WBC’s Make all data freely and electronically accessible (HMDB) Make all cmpds publicly available (HML)

6. Human Metabolome Project Purpose is to facilitate Metabolomics Objective is to improve Disease identification Disease prognosis & prediction Disease monitoring Drug metabolism and toxicology Linkage between metabolome & genome Development of software for metabolomics

7. HGP vs. HMP Focus on genome US/UK Effort 3,000,000,000 bases Public Repository (GenBank) Lots of pre-existing electronic data $1 billion Start 1990, end 2003 Focus on metabolome Canadian Effort 1400 compounds Public Repository (HMDB) Almost no pre-existing electronic records $7.5 million Start 2005, end 2008

8. Traditional Metabolite Analysis

9. Problems with Traditional Methods Requires separation followed by identification (coupled methodology) Requires optimization of separation conditions each time Often requires multiple separations Slow (up to 72 hours per sample) Manually intensive (constant supervision, high skill, tedious)

10. What’s the Difference Between Metabolomics and Traditional Clinical Chemistry? Throughput (more metabolites, greater accuracy, higher speed)

11. New Metabolomics Approaches

12. Newer Metabolomics Technologies

13. Coupled ES-IMS Systems

14. Advantages Measure multiple (10’s to 100’s) of metabolites at once – no separation!! Allows metabolic profiles or “fingerprints” to be generated Mostly automated, relatively little sample preparation or derivitization Can be quantitative (esp. NMR) Analysis & results in < 60 s

15. The HMDB & the HML HMDB is the public face of the HMP Freely web-accessible database providing detailed information on metabolites, chemistry, enzymes, diseases, pathways Links metabolome to genome HML is the Human Metabolome Library Repository of chemical samples for public redistribution Includes purchased, isolated & synthesized cmpds (many unique or rare cmpds)

16. Human Metabolome Database

17. The HMDB Allows One To… Learn more about the markers used in standard diagnoses Understand metabolism at many levels Link chemistry to genetics Link cmpd concentrations with disease Query and compare newly ID’d compounds with existing compounds Simulate the consequences of knock-outs or deletions on metabolic flux

18. The Human Metabolome Library

19. The HML Allows One To… Access rare or unusual metabolites as references or standards for MS, HPLC, GC-MS or NMR analyses Compare newly isolated compounds with known cmpds (saves on reinventing the wheel) Use these compounds as precursors to synthesize new metabolites Screen for potential transcr. modulators

20. Metabolic Profiling: The Possibilities Genetic Disease Tests Nutritional Analysis Clinical Blood Analysis Clinical Urinalysis Cholesterol Testing Drug Compliance Dialysis Monitoring MRS and fMRI Toxicology Testing Clinical Trial Testing Fermentation Monitoring Food & Beverage Tests Nutraceutical Analysis Drug Phenotyping Water Quality Testing Petrochemical Analysis

21. NMR Metabolic Profiling and Drug Toxicology

22. Genetic Disease Testing via NMR

23. 140+ Detectable Conditions Adenine Phosphoribosyltransferase Deficency Adenylosuccinase Deficiency Alcaptonuria a-Aminoadipic Aciduria b-Aminoisobutyric Aciduria a-Aminoketoadipic Aciduria Anorexia Nervosa Argininemia Argininosuccinic Aciduria Aspartylglycosaminuria Asphyxia Biopterin Disorders Biotin-responsive Multiple Carboxylase Deficiency Canavan’s Disease Carcinoid Syndrome Carnosinemia Cerebrotendinous Xanthomatosis/sterol 27-hydroxylaseDeficiency Citrullinemia Cystathioninemia Cystinosis Cystinuria (Hypercystinuria) Diabetes Dibasic Aminoaciduria

24. Applications in Clinical Analysis 14 propionic acidemia 11 methylmalonic aciduria 11 cystinuria 6 alkaptonuria 4 glutaric aciduria I 3 pyruvate decarboxylase deficiency 3 ketosis 3 Hartnup disorder 3 cystinosis 3 neuroblastoma 3 phenylketonuria 3 ethanol toxicity 3 glycerol kinase deficiency 3 HMG CoA lyase deficiency 2 carbamoyl PO4 synthetase deficiency 96% sensitivity and 100% specificity in ID of abnormal from normal by metabolite concentrations 95.5% sensitivity and 92.4% specificity in ID of disease or condition by characteristic metabolite concentrations 120 sec per sample

25. Applications in Cancer

26. Concluding Comments Metabolomics is here to stay Canada is actually leading the way in this field with several metabolomics companies and the Human Metabolome Project based entirely in Canada Think of the HMDB and the HML as new tools and reagents to do genomic research and to assist in diagnoses Characterized by rapidly evolving technologies (MS, NMR, MEMs, mFS)

27. Thanks to... Varian Inc.- has supported the development of Eclipse since 1998. Pfizer Global Research and Development entered into a strategic alliance with Chenomx in 2002 for the development and testing of Eclipse. They have renewed their commitment. AHFMR- has provided support through their Technology Commercialization program. Chenomx works with researchers from the University of Alberta and Alberta cancer Board (Polyomx Project) in their studies of metabolic profiling. Chenomx works with several clinical laboratories including Dynacare Kasper and the University of Alberta Hospital.Varian Inc.- has supported the development of Eclipse since 1998. Pfizer Global Research and Development entered into a strategic alliance with Chenomx in 2002 for the development and testing of Eclipse. They have renewed their commitment. AHFMR- has provided support through their Technology Commercialization program. Chenomx works with researchers from the University of Alberta and Alberta cancer Board (Polyomx Project) in their studies of metabolic profiling. Chenomx works with several clinical laboratories including Dynacare Kasper and the University of Alberta Hospital.

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