Download Gene-level median normalization

Of Men, Not Mice
Comparative analysis of human diseases
and mouse models
Wenzhong Xiao
Stanford Genome Technology Center
Massachusetts General Hospital, Harvard Medical School
Inflammation is a Common
Mechanism of Human Disease
Leading Causes of Deaths in the US (2015 CDC):
• Heart disease: 614,348
• Cancer: 591,699
• Chronic lower respiratory diseases: 147,101
• Accidents (unintentional injuries): 136,053
• Stroke (cerebrovascular diseases): 133,103
• Alzheimer's disease: 93,541
• Diabetes: 76,488
• Influenza and pneumonia: 55,227
• Nephritis, nephrotic syndrome, and nephrosis: 48,146
• Intentional self-harm (suicide): 42,773
Challenges in Studying Patients
• Ethical considerations
and regulations
• Heterogeneities of the
individuals: nature and
nurture
• Diversity of the disease:
etiologies & phenotypes
• Variations in patient
care
Disease Models
Patients
New insights into
disease mechanisms
and treatments
?
Molecular
Studies on
Model Organisms
Cellular
Phenotypical
Inflammation in Injury
To date, there have been >150 major clinical trials
testing agents to block inflammatory response in
critically ill patients and every one failed.
Critical Evaluation of Disease Models:
Reproducibility and Relevance to the Human Disease
Inflammation and the Host
Response to Injury consortium
• >100 participating investigators from 17 academic
institutions in the United States since 2001.
• To study systemic inflammation in humans by
monitoring multi-level information (genomics,
proteomics, cell function, physiological and clinical) of
trauma patients in intensive care units.
• Comparisons with murine models.
• http://igenomed.org/systemic_inflammation_of_hum
ans
How Well do
Animal Models
Reflect Human
Diseases?
Seok et al., PNAS, 2013
Comparisons of the
Time Course Response
between Human
Disease and Mouse
Models
Gene HLA-DRA as an Example
Correlations of Individual Pathways
Genomic Response to Severe Acute Inflammatory Diseases
in Human and Murine Models
http://igenomed.org/immune/
Why Existing Murine Models Poorly
Reflect Human Inflammatory Diseases?
• Ways existing disease models were
developed: phenotype(s) or genotype(s)
• Divergence of evolution of the immune
system between the species: resistance
vs tolerance
• Genetic distance between human and
mouse
Re-thinking the Animal
Models:
Are Mice Really
Miniaturized Humans?
from Shay et al., the Broad Institu
Since every drug compound acts on gene product(s),
disease studies in animal models need to show that the
molecular behavior of key genes and pathways in the
human disease is reproduced in the models used.
New Approaches Needed to Improve
Disease Models
Study
Patients
Clinical trials
based on
animal model
studies
Model
Systems
Generate new
hypotheses and
better models
)
Technologies for Host Resilience
New Computational Opportunities in
Patient Studies
Genome: Inherited and Somatic Variations
Epigenome and Transcriptome
Proteome and Metabolome
Cell biology
Organ/Tissue physiology
Microbiome
Environmentome
Clinical Information
Acknowledgements
•
•
•
•
•
•
•
•
•
Junhee Seok
Weihong Xu
Amit Kaushal
Hong Gao
Claire Ryu
Chia-Jung Chang
Erik Miller
Peng Li
Gonghua Li
• Wing H Wong, Stanford
• Rob Tibshirani, Stanford
• John Storey, Princeton
•
•
•
•
•
•
Trauma (Ron Maier, Harborview)
Burns (David Herndon, UTMB)
Endotoxin (Stephen Lowry, UMDNJ)
Cell Separation (Linc Moldawer, U Florida)
Microfluidics (Mehmet Toner, MGH)
Genomics (Ron Davis, Stanford, Henry Baker, U
Florida)
• Proteomics (Dick Smith, PNNL)
• Functional analysis (Carol Miller-Graziano, U
Rochester)
• Ron Tompkins (PI, MGH)
Questions &Comments?
[email protected]
http://igenomed.org/immune/
http://igenomed.org/immune/
http://igenomed.org/immune/
Comparisons of
Publicly Available
Studies of Severe Acute
Inflammatory Diseases
in Human and Murine
models
Species
Disease
Human
Mouse
GEO
R
Burns (reference)
GSE37069
1.
Trauma
GSE36809
0.
Endotoxemia
GSE3284
0.
Endotoxemia
GSE3284
0.
ARDS
GSE10474
0.
Sepsis
GSE13904
0.
Sepsis
GSE9960
0.
Sepsis
GSE13015
0.
Sepsis
GSE28750
0.
Acute Infection
GSE6269
0.
Burns
GSE7404
0.
Trauma
GSE7404
0.
Endotoxemia
GSE7404
0.
Endotoxemia
GSE5663
0.
ARDS
GSE19030
-0.
Sepsis
GSE5663
0.
Sepsis
GSE5663
0.
Sepsis
GSE19668
0.
Sepsis
GSE26472
0.
Infection
GSE20524
0.
Commonalities of Inflammatory Response
to Different Injuries in Patients
Time course studies of 167 patients up to 28 days after
severe blunt trauma and 244 patients up to 1 year after
burn injury.
Burn
R2=0.91
97%
Trauma
Gene MMP8 as an Example
0 Hour
1 Day
1 Week
1 Month
1 Year