JenaSysBio.ppt

8/13/2019 JenaSysBio.ppt

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Systems Biology in

Bioscience and Medicine

DGKL/ÖGLMK – Jena, Oct. 7, 2005David Wishart, University of Alberta

[email protected]



Genomics, Proteomics &

Systems Biology

1990 1995 2000 2005 2010 2015 2020

Genomics

Proteomics

Systems Biology



What is Systems Biology?

• Systems Biology - Systems biologyis the study of an organism, viewed asan integrated and in teract ing network of genes, proteins and biochemicalreactions. The integration of genomics,proteomics, metabolomics & modeling

• The Goal: Predic t ive, Preventative andPersonal ized Medicine -- Leroy Hood



What’s it good for?

• Basic Science/”Understanding Life”

• Predicting Phenotype from Genotype

•

Understanding/Predicting Metabolism• Understanding Cellular Networks

• Predicting Disease Outcome/Prognosis

• Understanding Pathogenicity/Toxicity• Predicting Adverse Drug Reactions

• Improving Medical Efficiency/Efficacy



Systems Biology isMultidisciplinary





Different Ways of Viewing

the World• Physicists

• Chemists

• Biologists



A Fundamental Difference

• What happens if I drop this ball? – Phys ics -- predict ive

•

What happens if I mix this acid withthat base? – Chem istry -- predict ive

• What happens if this TGF receptor isphosphorylated? – Bio logy -- observational



THE Grand Challenge…

Making B ioscience & Medic ine Predict ive Sciences



How To Do

This?



Going From “Omics” to

“Metrics” • Genomics Genometrics

• Proteomics Proteometrics

• Metabolomics Metabometrics

• Phenomics Phenometrics

• Bioinformatics Biosimulation

• Quanti fy, quan t i fy, quan t i fy



Going From Networks in v ivo to Networks in si l ico



Going From Model Systemsto Medicine



Systems Biology in Medicine•

Still in its infancy… • Ethnopharmacology & traditional meds

• Integrated biodiagnostics (combined

microarray, ICAT-MS and metabolite“profiles” – multicomponent biomarkers)

• Adverse drug response prediction and

monitoring (personalized medicine)• Understanding complex metabolic

diseases (cachexia, obesity, diabetes)

Clinical Lab Medicine Leads the Way



The Pyramid of Life

25,000 Genes

2500 Enzymes

1400Chemicals

Metabolomics

Proteomics

Genomics



Why Are MetabolitesRelevant?

Metabolites are the Canaries of the Genome



Human Metabolome Project

• $7.5 million Genome Canada Projectlaunched in Jan. 2005

• Mandate to quantify (normal andabnormal ranges) and identify allmetabolites in urine, CSF, plasma andWBC’s

• Make all data freely and electronicallyaccessible (HMDB)

• Make all cmpds publicly available (HML)



Traditional Metabolite

Analysis

HPLC, GC, CE, MS



New MetabolomicsApproaches



The HMDB & the HML

• HMDB is the publicface of the HMP

• Freely web-

accessible databaseproviding detailedinformation onmetabolites,

chemistry, enzymes,diseases, pathways

• Links metabolometo genome

• HML is the HumanMetabolome Library

• Repository of

chemical samplesfor publicredistribution

• Includes purchased,

isolated &synthesized cmpds(many unique orrare cmpds)







Metabolic Modeling

Atomic Scale0.1 - 1.0 nmCoordinate dataDynamic data0.1 - 10 nsMolecular dynamics

Meso Scale1.0 - 10 nmInteraction dataKon, Koff, Kd10 ns - 10 msMesodynamics

Continuum Model10 - 100 nmConcentrationsDiffusion rates10 ms - 1000 sFluid dynamics



SimCell

http:/ /wishart.biology.ualberta.ca/SimCell/



Acetyl-CoA

Citrate

Isocitrate

-Ketoglutarate

Succinyl-CoASuccinate

Fumarate

L-Malate

Oxaloacetate

Glycerol Pyruvate

Acetate

1

2

Succinate dehydrogenase

Fumarate Reductase

The TCA Cycle & SimCell



Succinate Production

Observed Predicted (SimCell)



The Human Metabolome

Library

10 mg – 10 g of ~1400 human metabolites



The HML Allows One To…

• Access rare or unusual metabolites asreferences or standards for MS, HPLC,GC-MS or NMR analyses

• Compare newly isolated compoundswith known cmpds (saves onreinventing the wheel)

• Use these compounds as precursors tosynthesize new metabolites

• Screen for potential transcr. modulators



Metabolic Profiling: ThePossibilities

• 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



-25

-20

-15

-10

-5

0

5

10

15

20

25

-30 -20 -10 0 10

PC1

PC2

PAP

ANIT

Control

ANIT

PAP

Control

Principal Component Analysis

NMR Metabolic Profiling and

Drug Toxicology



Genetic DiseaseTesting via NMR



140+ Detectable Conditions Adenine

PhosphoribosyltransferaseDeficency

Adenylosuccinase Deficiency

Alcaptonuria

-Aminoadipic Aciduria

b-Aminoisobutyric Aciduria

-Aminoketoadipic Aciduria

Anorexia Nervosa

Argininemia

Argininosuccinic Aciduria

Aspartylglycosaminuria

Asphyxia

Biopterin Disorders

Biotin-responsive MultipleCarboxylase Deficiency

Canavan’s Disease

Carcinoid Syndrome

Carnosinemia

CerebrotendinousXanthomatosis/sterol 27-hydroxylaseDeficiency

Citrullinemia

Cystathioninemia

Cystinosis

Cystinuria (Hypercystinuria)

Diabetes

Dibasic Aminoaciduria

Dicarboxylic Aminoaciduria

Dichloromethane Ingestion

Dihydrolipoyl DehydrogenaseDeficiency

DihydropyrimidineDehydrogenase Deficiency

DimethylglycineDehydrogenase Deficiency

Essential Fructosuria

Ethanolaminosis

Ethylmalonic Aciduria Familial Iminoglycinuria

Fanconi’s Syndrome

Folate Disorder

Fructose Intolerance

Fulminant Hepatitis

Fumarase Deficiency

Galactosemia

Glucoglycinuria

Glutaric Aciduria Types 1 & 2

Glutathionuria

Glyceroluria (GKD)

D-Glyceric Aciduria

Guanidinoacetate-Methyltransferase Deficiency

Hartnup Disorder

Hawkinsinuria

Histidinemia

Histidinuria

Homocystinsufonuria

Homocystinuria

4-Hydroxybutyric Aciduria

2-Hydroxyglutaric Aciduria

Hydroxykynureninuria

Hydroxylysinemia

Hydroxylysinuria

3-Hydroxy-3-methylglutaric Aciduria 3-Hydroxy-3-methylglutaryl-Co A

Lyase Deficiency

Hydroxyprolinemia

Hyperalaninemia

Hyperargininemia (Argininemia)

Hyperglycinuria

Hyperleucine-Isoleucinemia

Hyperlysinemia

Hyperornithinemia Hyperornithinemia-

Hyperammonemia-HomocitrullinuriaSyndrome (HHH)

Hyperoxaluria Types I & 2

Hyperphenylalaninemia

Hyperprolinemia

Hyperthreoninemia



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 metaboliteconcentrations

• 120 sec per sample Clinical Chemistry 47, 1918-1921 (2001).





Summary

• Systems Biology requires the integrationof data archiving, experimentation andnovel computational approaches

• Some of the first applications of systemsbiology to medicine will involve linkingmetabolomics with clinical chemistry

• New modeling approaches are emergingthat are making bioscience and medicine“predictive”



Danke...

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JenaSysBio.ppt