Dr. Leroy Hood Lecuture on P4 Medicine

Systems Biology and Systems Medicine: Catalyzing a Revolution from Reactive to Proactive (P4) MedicinePredictive, Personalized, Preventive and Participatory
Lee Hood
Institute for Systems Biology, Seattle

I Participated in Four Paradigm Changes in Biology Leading to P4 Medicine
Bringing engineering to biology (high throughput biology)
The human genome project
Cross-disciplinary biology
Systems biology
Predictive, Preventive, Personalized, and Participatory medicine (P4 Medicine)
Each fundamentally changed how we think about biology and medicine.
Each was met initially with enormous skepticism.
Each new idea needed new organizational structure.

Contemporary Systems Biology is Predicated on Viewing Biology is an Informational Science

There are Two Types of Biological Information that
Can Lead to Disease
Thedigital informationof the genome
The environmental information that impinges upon and modifies the digital information

Two General Biological Structures that Handle Information
Biological networks capture, transmit, process and pass on information
Simple and complex molecular machines execute biological functions

Left Index Fingerprints from Identical Twins

ISB’s View of Systems Biology

Agenda: Use biology to drive technology and computation. Need to create a cross-disciplinary culture.
Biological Information
BIOLOGY
Cross-Disciplinary
Culture
Team Science
Biology
Chemistry
Computer Science
Engineering
Mathematics
Physics
TECHNOLOGY
COMPUTATION

Essentials of Systems Biology
Hypothesis-driven
Global data acquisition
Integrate different types of data
Delineate biological network dynamics
Formulate models that are predictive and actionable.

A Systems View of Disease

dynamics of
pathophysiology
diagnosis
therapy
prevention
A Systems View of Medicine Postulates that Disease Arises from Disease-
Perturbed Networks
Non-Diseased
Diseased

A Systems Approach to Prion Disease in Mice

Prion disease example:Prion Protein Exists in Two Forms
PrP Genetic Mutations
PrPSc Infections
Spontaneous conversion
Cellular PrPC
Infectious PrPSc

Global TranscriptomeAnalysis—Differentially Expressed Genes (DEGs)
Time-course array analysis:
subtrative analyses to DEGs
C57BL/6J-RML: 12 time points
FVB/NCr-RML: 11 time points
BL6.I-301V: 9 time points
FVB/B4053-RML: 8 time points
Inoculate w/ Prions
Prion strains:
RML
301V
Mouse strains:
C57BL/6J
FVB/NCr
BL6.I
FVB/B4053
Prion infected brain
RNA
from brain
homogenate
Almost 50 million
Data points
Mouse Genome array:
45,000 probe sets
~22,000 mouse genes.
Uninfected brain
Carlson lab
Inyoul Lee (Brianne Ogata, David Baxter)
Bruz Marzolf (Microarray Facility)

Prion Disease in Eight Mouse Strains: dealing with the signal to noise challenge
employing subtractive biology
Differentially Expressed Genes--DEGs--7400 to 333

Neuropathology Identifies 4 Networks
Microglia / Astrocyte
activation
PrP accumulation
Synaptic Degeneration
Nerve cell death
Infected
Normal

Integration of Six Data Types for Prion Disease Studies in Mice
Deep brain transcriptome analyses at 10 time points across disease onset in 8 mouse strains
Correlate with protein interaction data from known (histopathology) disease-perturbed networks
Correlation with dynamical histopathologicalstudies
Correlation with clinical signs
Distribution of infectious prion protein in the brains across disease progression
Brain-specific blood protein concentration changes

Dynamics of Prion Accumulation Network in the Brain: 6 weeks, 10 weeks and 20 weeks of 22 week course

PrP accumulation and replication network—6 weeks

Sequential Disease-Perturbation of the Four Networks of Prion Disease
18~20 wk
22 wk
0 wk
Clinical Signs
Prion
accumulation
Glial
Activation
SynapticDegeneration
Neuronal
Cell Death
Na+
channels
Reactive
Astrocytes
Cholesterol
transport
Caspases
Sphingolipid
synthesis
Cargo
transport
Leukocyte
extravasation
Lysosome
proteolysis
*Arachidonate
metab./Ca+ sig.

333 DEGs encode core prion disease
231/333 DEGs encode known disease pathogenic networks
102/333 DEGs encode novel pathogenic networks--the dark genes of prion disease
Disease-perturbed networks sequentially activated
Re-engineer disease-perturbed networks with drugs—new approach to drug target discovery
Implications for systems diagnostics
DEGs Encoding Known and Novel Prion Disease Phenotypes

A Systems Approach to Blood Diagnostics

Organ-Specific Blood FingerprintsMaking Blood A Window Distinguishing Health and Disease
Blood Vessel

Organ-specific Protein Blood Fingerprints—Disease Diagnostics
Early detection
Disease stratification
Disease progression
Follow therapy
Assess reoccurances
Integrated Diagnostics—platform company for P4 medicine

Strategies and Technologies: Exploring New Dimensions of Data Space

Whole Genome Sequencing of Families: New Genomic Strategy

Whole Genome Sequencing of Family of Four
Unaffected parents
Children with craniofacial
Malformation (Miller Syndrome)
and lung disease (ciliary dyskinesia)
Noise reduction power of a family sequence permits:
Identify 70% sequencing errors using principles of Mendelian genetics — ~1/100,000 error rate
Discovery of ~230,000 novel (rare) SNPs—4.2 million SNPs in family
Reduced disease gene candidates to 4

Microfluidic Protein Chip:Assay 2500 Organ-Specific Blood Proteinsfrom Millions of Patients Using a Drop of Blood
Jim Heath--Caltech

DEAL for In vitro molecular diagnostics:
Integrated nanotech/microfluidics platform
300 nanoliters of plasma
cells out
Assay region
Organ 1
Organ 2
Tox response
inflammation
Dynamic range—106
Sensitivity--high atmole
5 minute measurement
Jim Heath, et al

Patient Assays that Explore New Dimensions of Data Space

Individual Patient Information-Based Assays of the Present/ Future (I)
Genomics
Complete individual genome sequences—predictive health history—will be done sequencing families
Complete individual cell genome sequences—cancer.
Complete MHC chromosomal sequence in families—autoimmune disease and allegies
200 Actionable single-nucleotide polymorphisms (SNPs)—pharmacogenetics-related and disease-related genes
Sequence 1000 transcriptomessimultaneously in one DNA sequencing run from single cancer cells to identify quantized cells states and dissect cancer
Analyze aging transcriptome profiles
Proteomics
2500 blood organ-specific blood proteins from 300 nanoliters of blood in 5 minutes—twice per year (50 proteins from 50 organs)—wellness assessment.
Array of 13,000 human proteins—against autoimmune or allergic sera--stratify.
Single molecule protein analyses—blood organ-specific proteins

Individual Patient Information-Based Assays of the Present/ Future (II)
Single cells
Analyze 10,000 B cells and 10,000 T cells for the functional regions of their immune receptors—past and present immune responsiveness—follow vaccinations—identify autoimmune antibodies.
Analyze individual blood macrophages—inflammation, etc.
Use molecular-pore technology to separate epithelial cells from blood cells--cancer
iPS (stem) cells
Analyze individual stem (iPS) cells from each individual differentiated to relevant tissues to get important phenotypic information—molecular, imaging and higher level phenotypic measurements.

35
Predictive, Personalized, Preventive and Participatory (P4) Medicine
Driven by systems approaches to disease, new measurement (nanotechnology) and visualization technologies and powerful new computational tools, P4 medicine will emerge over the next 10-20 years

P4 Medicine
Predictive:
Probabilistic health history--DNA sequence
Biannual multi-parameter blood protein measurements
In vivo molecular imaging

P4 Medicine
Personalized:
Unique individual human genetic variation mandates individual treatment
Patient is his or her own control—longitudinal data
Billions of data points on each individual
100s millions patients
with billions data points

P4 Medicine
Preventive:
Design of therapeutic and preventive drugs
via systems approaches
Systems approaches to vaccines will transform prevention of infectious diseases
Transition to wellness assessment

P4 Medicine
Participatory:
Patient understands and participates in medical choices
Physicians trained before P4 will have to understand it
Medical community—interconnected and educated
Create IT for healthcare to handle billions of patients, each with billions of data points

Digitalization of Biology and Medicine Will Transform Medicine
Analysis of single molecules, single cells, single organs and single individuals
A revolution that will transform medicine even more than digitalization transformed information technologies and communications
Digitization of medicine will lead to dramatically lower healthcare costs
Single individual
Single cell
Single molecule

ISB Strategic Partnerships for P4 Medicine

ISB’s Two-Fold Strategy for P4 Medicine and Strategic Partnerships
Inventing strategies, technologies and computational tools—ISB/Luxembourg
Creating the P4 Medicine Institute to be an innovative advocate in bringing P4 medicine to patients--ISB/OSU

The P4 Medicine Institute (ISB/OSU)
Goal is to catalyze the P4 medical transformation of healthcare by:
Accelerating translation of systems science to clinical practice
Executing tangible & pragmatic demonstration projects—lung cancer and wellness
Developing public-private industry collaboration
Addressing technical, strategic, operational, policy, economic, & sociologic issues
Science & Technology
+
Policy & Industry

Six Assertions About P4 Medicine
P4 medicine is medicine of the present/near future
Proactive P4 medicine is revolutionary rather than incremental or evolutionary—medicine is becoming an information science. Generate billions of data points on each individual.
P4 medicine will transform the healthcare industry.
P4 medicine will be effective and inexpensive.
Pilot projects with informational assays in patient groups will be necessary to convince skeptics.
The national healthcare debate in the future should be reframed around P4 medicine rather than the old reactive medicine.

Acknowledgements
Prion--Institute for Systems Biology
Daehee Hwang
Inyoul Lee
HyuntaeYoo
Eugene Yi (proteomics core facility)
BruzMarzolf (Affymetrix core facility)
Nanotechnology—protein chips, protein-capture agents--Jim Heath, Caltech
MRM protein assays—R Moritz, R Aebersold
Single-cell analyses—Leslie Chen and QiangTian
Luxemburg Strategic Partnership—David Galas, Diane Isonaka, Rudi Balling (Lux)
Prion--McLaughlin Research Institute
Great Falls, Montana
RanjitGiri
Douglas Spicer
Rajeev Kumar
Rose Pitstick
Rebecca Young
George A. Carlson
Family genome project—ISB/UW/Utah/Complete Genomics—David Galas
P4MI Institute—Fred Lee, Clay Marsh (OSU)
Single protein analysis—Chris Laustead

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Dr. Leroy Hood Lecuture on P4 Medicine

by The Ohio State University Wexner Medical Center on May 14, 2010

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