Systems Biology in Bioscience and Medicine

1
Systems Biology in Bioscience and Medicine

• DGKL/ÖGLMK Jena, Oct. 7, 2005
• David Wishart, University of Alberta
• david.wishart_at_ualberta.ca

2
Genomics, Proteomics Systems Biology
Genomics
Proteomics
Systems Biology
3
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

4
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

5
Systems Biology is Multidisciplinary
6
and Multi-instrumental
Computer Cluster
HT-NMR
FT-MS
Affy Scanner
HPLC
7
Different Ways of Viewing the World

• Physicists
• Chemists
• Biologists

8
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

9
THE Grand Challenge
Making Bioscience Medicine Predictive Sciences
10
How To Do This?
11
Going From Omics to Metrics

• Genomics Genometrics
• Proteomics Proteometrics
• Metabolomics Metabometrics
• Phenomics Phenometrics
• Bioinformatics Biosimulation
• Quantify, quantify, quantify

12
Going From Networks in vivo to Networks in silico
13
Going From Model Systems to Medicine
14
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
15
The Pyramid of Life
Metabolomics Proteomics Genomics
1400 Chemicals
2500 Enzymes
25,000 Genes
16
Why Are Metabolites Relevant?
Metabolites are the Canaries of the Genome
17
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)

18
Traditional Metabolite Analysis
HPLC, GC, CE, MS
19
New Metabolomics Approaches
20
The HMDB the HML

• HML is the Human Metabolome Library
• Repository of chemical samples for public
  redistribution
• Includes purchased, isolated synthesized cmpds
  (many unique or rare cmpds)

• 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

21
Human Metabolome Database
www.hmdb.ca
22
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 knock-outs or
  deletions on metabolic flux

23
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 Diffusi
on rates 10 ms - 1000 s Fluid dynamics
24
SimCell
http//wishart.biology.ualberta.ca/SimCell/
25
The TCA Cycle SimCell
Acetate
Acetyl-CoA
Glycerol
Pyruvate
Oxaloacetate
Citrate
Isocitrate
L-Malate
?-Ketoglutarate
Fumarate
2
1
Succinate dehydrogenase
Succinate
Succinyl-CoA
26
Succinate Production
Observed Predicted (SimCell)
27
The Human Metabolome Library
10 mg 10 g of 1400 human metabolites
28
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

29
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

30
NMR Metabolic Profiling and Drug Toxicology
Principal Component Analysis
31
Genetic Disease Testing via NMR
32
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
• Canavans Disease
• Carcinoid Syndrome
• Carnosinemia
• Cerebrotendinous Xanthomatosis/sterol
  27-hydroxylaseDeficiency
• Citrullinemia
• Cystathioninemia

• 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)

• 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-Homocitrullinuria
  Syndrome (HHH)

33
Applications in Clinical Analysis

• 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

• 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

Clinical Chemistry 47, 1918-1921 (2001).
34
Applications in Cancer
Acetic Acid Betaine Carnitine Citric
Acid Creatinine Dimethylglycine Dimethylamine Hipp
ulric Acid Lactic Acid Succinic
Acid Trimethylamine Trimn-N-Oxide Urea Lactose Sub
eric Acid Sebacic Acid Homovanillic
Acid Threonine Alanine Glycine Glucose
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
Metabolic Microarray - 35 min.
35
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

36
Danke...