Systems Biology in Bioscience and Medicine

DGKL/GLMK Jena, Oct. 7, 2005

David Wishart, University of Alberta david.wishart@ualberta.ca

Genomics, Proteomics & Systems Biology

Genomics

Proteomics

Systems Biology 1990 1995 2000 2005 2010 2015 2020

What is Systems Biology?

Systems Biology - Systems biology
is the study of an organism, viewed as an integrated and interacting network of genes, proteins and biochemical reactions. The integration of genomics, proteomics, metabolomics & modeling

The Goal: Predictive, Preventative and

Personalized Medicine -- Leroy Hood

Whats 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 is Multidisciplinary

and Multi-instrumental
Computer Cluster HT-NMR

FT-MS HPLC Affy Scanner

Different Ways of Viewing the World Physicists Chemists

Biologists

A Fundamental Difference
What happens if I drop this ball?
Physics -- predictive

What happens if I mix this acid with that base?

Chemistry -- predictive

What happens if this TGF receptor is phosphorylated?

Biology -- observational

THE Grand Challenge

Making Bioscience & Medicine Predictive Sciences

How To Do This?

Going From Omics to Metrics

Genomics Proteomics Metabolomics Phenomics Bioinformatics Genometrics Proteometrics Metabometrics Phenometrics Biosimulation

Quantify, quantify, quantify

Going From Networks in vivo to Networks in silico

Going From Model Systems to 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

Metabolomics
1400 Chemicals

Proteomics
2500 Enzymes

Genomics

25,000 Genes

Why Are Metabolites Relevant?

Metabolites are the Canaries of the Genome

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 WBCs Make all data freely and electronically accessible (HMDB) Make all cmpds publicly available (HML)

Traditional Metabolite Analysis

HPLC, GC, CE, MS

New Metabolomics Approaches

The HMDB & the HML

HMDB is the public face of the HMP Freely webaccessible 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)

Human Metabolome Database

www.hmdb.ca

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 IDd compounds with existing compounds Simulate the consequences of knockouts or deletions on metabolic flux

Metabolic Modeling

Atomic Scale 0.1 - 1.0 nm Coordinate data Dynamic data 0.1 - 10 ns Molecular dynamics

Meso Scale 1.0 - 10 nm Interaction data Kon, Koff, Kd 10 ns - 10 ms Mesodynamics

Continuum Model 10 - 100 nm Concentrations Diffusion rates 10 ms - 1000 s Fluid dynamics

SimCell

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

The TCA Cycle & SimCell

Acetate Glycerol Pyruvate Oxaloacetate Acetyl-CoA Citrate

L-Malate

Isocitrate

Fumarate
Fumarate Reductase

-Ketoglutarate 2 1 Succinate Succinyl-CoA

Succinate dehydrogenase

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 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

Metabolic Profiling: The Possibilities

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

NMR Metabolic Profiling and Drug Toxicology

25

PAP

PC2
20 15 10 5

ANIT

ANIT

0 -5 -10

Control PAP
PC1 -20 -10 0 10

Control

-15 -20 -25 -30

Principal Component Analysis

Genetic Disease Testing via NMR

140+ Detectable Conditions

Adenine Phosphoribosyltransferase Deficency Adenylosuccinase Deficiency Alcaptonuria -Aminoadipic Aciduria b -Aminoisobutyric Aciduria -Aminoketoadipic Aciduria Anorexia Nervosa Argininemia Argininosuccinic Aciduria Aspartylglycosaminuria Asphyxia Biopterin Disorders Biotin-responsive Multiple Carboxylase Deficiency Canavans Disease Carcinoid Syndrome Carnosinemia Cerebrotendinous Xanthomatosis/sterol 27hydroxylaseDeficiency Citrullinemia Cystathioninemia Cystinosis Cystinuria (Hypercystinuria) Diabetes Dibasic Aminoaciduria Dicarboxylic Aminoaciduria Dichloromethane Ingestion Dihydrolipoyl Dehydrogenase Deficiency Dihydropyrimidine Dehydrogenase Deficiency Dimethylglycine Dehydrogenase Deficiency Essential Fructosuria Ethanolaminosis Ethylmalonic Aciduria Familial Iminoglycinuria Fanconis Syndrome Folate Disorder Fructose Intolerance Fulminant Hepatitis Fumarase Deficiency Galactosemia Glucoglycinuria Glutaric Aciduria Types 1 & 2 Glutathionuria Glyceroluria (GKD) D-Glyceric Aciduria GuanidinoacetateMethyltransferase 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 HyperornithinemiaHyperammonemia-Homocitrullinuria Syndrome (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 metabolite concentrations 120 sec per sample

Clinical Chemistry 47, 1918-1921 (2001).

Applications in Cancer
Normal Below Normal Above Norrmal Absent Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12 Patient 13 Patient 14 Patient 15
Acetic Acid Betaine Carnitine Citric Acid Creatinine Dimethylglycine Dimethylamine Hippulric Acid Lactic Acid Succinic Acid Trimethylamine Trimn-N-Oxide Urea Lactose Suberic Acid Sebacic Acid Homovanillic Acid Threonine Alanine Glycine Glucose

Metabolic Microarray - 35 min.

Summary
Systems Biology requires the integration of data archiving, experimentation and novel computational approaches Some of the first applications of systems biology to medicine will involve linking metabolomics with clinical chemistry New modeling approaches are emerging that are making bioscience and medicine predictive

Danke...