Medicine of the Future—The Transformation from Reactive to

Proactive (P4) Medicine

Predictive, Personalized, Preventive and Participatory

Lee Hood

Institute for Systems Biology, Seattle

The Current Healthcare Debate• The debate is centered on medicine of the past/present

rather than medicine of the future• Healthcare is a fundamental right of all citizens. When

viewed in the context of medicine of the present--current health care is ineffective, costly and therefore impossible to extend to all citizens

• The healthcare debate today is about rationing and who will be left out or poorly served

• The key is to understand medicine of the near future (P4 medicine) and realize the transformation it will bring—an effectiveness and reduced cost—ultimately with the possibility of bringing adequate healthcare to all

Contemporary Systems Biology is Predicated on Viewing Biology

is an Informational Science

• The digital information of the genome

There are two types of Biological Information

• The environmental information that impinges upon and modifies the digital information.

Biological Structures that Handle Information

• Biological networks capture, transmit, process and pass on information– Protein networks– Gene regulatory networks– MicroRNA networks– Genetic networks

• Simple and complex molecular machines--execute biological functions

Most Sophisticated Integrated Biological Network Defined to Date

DNA

mRNA

Protein

Protein interactions and biomodules

Protein and gene networks

Cells

Phenotypes

Organs

Individuals

Populations

Ecologies

Hierarchical or Multiscalar Levels of Biological Information

A Systems Approach to Prion Disease in Mice

Prion disease example:Prion Protein Exists in Two Forms

Cellular PrPC PrP Genetic Mutations

PrPSc Infections

Spontaneous conversion

Infectious PrPSc

Global Transcriptome Analysis

Uninfected brain

Prion infected brain

Inoculate w/ Prions

Time-course array analysis:

Mouse Genome array:45,000 probe sets

~22,000 mouse genes.

RNARNAfrom brainfrom brain

homogenatehomogenate

Prion strains:• RML• 301V

Mouse strains: C57BL/6J FVB/NCr BL6.I FVB/B4053

C57BL/6J-RML: 12 time points

FVB/NCr-RML: 11 time points

BL6.I-301V: 9 time points

FVB/B4053-RML: 8 time points

Almost 46 millionData points

Carlson labInyoul Lee (Brianne Ogata, David Baxter)Bruz Marzolf (Microarray Facility)

Multiple groups:five inbred strains, two transgenic strains and one knockout strain

Group

Mouse

Prnp Genotype

Prion Strain

Incubation Time (d)

1 C57BL/6J a/a RML ~150 2 B6.I-1 b/b 301V ~120 3 FVB/NCr a/a RML ~150 4 B6.I-1 b/b RML ~350 5 C57BL/6J a/a 301V ~260 6 (FVB x FVB.129-Prnptm1Zrch) a/0 RML ~400 7 Tg(MoPrP-A)B4053 30 x a RML ~60 8 FVB.129-Prnptm1Zrch 0/0 RML No illness

Differentially Expressed Genes--DEGs--7400 to 333

Examples of Prion Subtractive Transcriptional Analyses

• Control vs disease-infected animals at 10 time points across disease progression in 8 mouse strains

• Subtract unique responses in 3 inbred strains• Subtract responses from differing levels of prion

proteins in transgenic/heterozygotic animals• Subtract differences from infection with two different

prion strains• Subtract unique contributions for long and short period

disease incubations• Subtract differences arising in infected prion knockout

animals (no disease)

Neuropathological FeaturesPrP accumulation Microglia / Astrocyte

activation

Synaptic Degeneration

Normal Infected

Nerve cell death

Integration of Different Types of Information

• Subtractive dynamic transcriptome analyses• Network dynamics of relevant brain networks• Dynamic histopathology of the brain• Dynamic distribution of infectious prion particles

in the brain• Onset of clinical symptoms

PrP accumulation network

DEGs Encoding Known and Novel Prion Disease Phenotypes

• 231/333 DEGs encode known disease pathogenic networks• 102/333 DEGs encode novel pathogenic networks--the dark genes of prion

disease– Androgenic steroid metabolism– Iron metabolism– Arachidonate/prostaglandin metabolism

• Three of the four prion-disease networks are seen in Alzheimer's disease--prion replication and accumulation is unique

• This study has interesting implications for thinking about drug targets for neurodegenerative diseases

• Implications for systems diagnostics

A Systems Approach to Blood Diagnostics

Dynamics of a Prion Perturbed Network in Mice

Nerve cell death

•Organ-specific transcripts now identified for 50+ individual organs in mouse and humans.

•We have identified more than 200 brain-specific transcripts

A Genomics Approach to the Identification of Organ-Specific Transcripts

Organ-specific secreted protein mRNAtpmtpm

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

Blood Vessel

Presymptomatic Diagnosis of Murine Prion Disease with Organ-Specific

Protein in Blood Samples15/45 brain-specific blood proteins enabled early detection

Clinical Signsat 18 wkPresymptomatic

Diagnosis at 10 wk

Organ-specific Protein Blood Fingerprints—Disease Diagnostics

• Early detection

• Disease stratification

• Disease progression

• Follow therapy

Technologies Will Create New Patient Data Spaces to be Explored

and Will Greatly Expand the Old Patient Data Spaces

What are the technologies that will transform systems or P4 medicine?

• High throughput DNA sequencing for individual human genome sequencing

• Targeted MRM mass spectrometry for discovery, validation and typing (initially) of blood fingerprints

• Microfluidic protein chip to measure blood organ-specific protein fingerprints and type millions of individuals

• New chemistry for protein-capture agents

• Single-cell analyses--deciphering the interplay of the digital genome and the environment

• In vivo and in vitro molecular imaging to assess disease distribution and follow therapy

Genome Sequencing of Individuals

Study Families to Suppress Noise and Carry out Powerful New Genetic Analyses

Unaffected parents

Children with craniofacialmalformation and lungdisease

Lynn Jorde and Michael Bamshad: family DNA—Sequencing by Complete Genomics, Inc

Advantages of Sequencing a Family

• Low error rate—1/105

• 340,000 new SNPs (4.2 million SNPs total)• Recombinational maps of children’s

genomes• Inter-generational mutation rates• Narrow down disease gene candidates for

two diseases in children to three genes

0

50

100

150

200

250

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

x

x

x

Both children inherited the same allele from both parentsEach child inherited a different allele from each parentChildren inherited the same allele from dad, different alleles from momChildren inherited the same allele from mom, different alleles from dad

X

65 crossovers in (2) male meioses (left)104 crossovers in (2) female meioses (right)

Recominational Genome Map from Miller’s Syndrome Children

Microfluidic Protein Chip

DEAL for In vitro molecular diagnostics:

Integrated nanotech/microfluidics platform

Jim Heath, et al

Organ 1Organ 1 Organ 2Organ 2 Tox responseTox response inflammationinflammation

cells out

300 nanoliters of plasma

Assay region

Dynamic range--108

Sensitivity--high atmole

5 minute measurement

New Approach to Protein-Capture Agents

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Antibody Displacement Technology

Protein Catalyzed Capture Agents:• triligands determined by repeated screening of target protein across synthetic bead-

bound peptide libraries• anchor peptide is selected on the first screen• protein catalyzes the formation of second ligand to anchor ligand on second screen• protein catalyzes the formation of the third ligand to the anchor and second ligand

on third screen• high affinity, stable and easily manufactured triligand capture agents

An example of a triligand PCC agent for bovine carbonic anhydrase II

Single-Cell Analyses

Multiplexed ELISA for secreted proteins

Single Cell Analyses

Adrian Ozinsky

Routine Analyses on Individual Patients with 10 years

Individual Patient High Throughput Assays of the Future

• Complete individual genome sequences—predictive health history—will be done sequencing families

• Sequence 1000 transcriptomes simultaneously in one DNA sequencing run from single cancer cells or single cells from biopsies--to stratify disease.

• 2500 blood organ-specific blood proteins—twice per year (50 proteins from 50 organs)—wellness assessment.

• 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.

• Analyze individual stem (iPS) cells from each individual differentiated to relevant tissues to get important phenotypic information—molecular and imaging.

Organ-Specific Blood Protein Fingerprint Analyses Will Transform

Biology and Medicine

Applications of Organ-Specific Blood Protein Fingerprints

• Disease diagnostics--early, stratification, progression, follow therapy

• Interactions of multiple organs in studying therapeutic responses, drug toxicity and biology

• Identification of disease-perturbed networks as a prelude to drug target identification

• Assessing the use of drugs in individuals--toxicity, response, dose, combinatorial therapies

• Wellness assessment--longitudinal data gathering – patient is their own control

• Do human biology from the blood--aging, development, physiological responses

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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

–Billions of data points on each individual

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

–Patient increasing will make choices with doctor intervention

Will impact the health care system significantly:

• Pharmaceuticals

• Biotechnology

• Diagnostics

• IT for healthcare

• Healthcare industry

• Health insurance

• Medicine--diagnostics, therapy, prevention, wellness

• Nutrition

• Assessments of environmental toxicities

• Academia and medical schools

P4 Medicine Will Transform the Health Care Industry

Healthcare System

Fundamentally new ideas need New organizational structures

Digitalization of Biology and Medicine Will Transform Medicine

• Analysis of single molecules, single cells 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

Why the Digitalization of Medicine and P4 (Systems) Medicine Will

Reduce Healthcare Costs• Diagnosis will stratify disease and impediance match

drugs

• Re-engineering disease-perturbed networks to normalicy with drugs—new and less expensive strategy for drug target discovery

• Survey wellness with 2500 blood organ-specific protein measurements biannually—global early detection

• Technologies exponentially increasing in the number of measurements they can make and decreasing in cost

• Other medical advances arising from mechanistic insights—stem cells, neurodegenerative, aging, vaccines, cancer etc.

Inventing the Future

20th Century Biomedicine 21st Century BiomedicineISB•Analyzing one gene and one

small problem at a time• Systems analysis of biology and

medicine--e.g., predictive, preventive, personalized and participatory (P4) medicine

• Technology development

• Pioneer computational tools

• Transferring knowledge to society--joining academics and industry--changing K-12 science education--P4 medicine and society

• Strategic partnerships--for hard scientific problems--P4 medicine--

industrial, academic, government, international

ISB Strategic Partnerships to Hasten the Realization of P4

Medicine

Advantages of National and International Strategic Partnerships

• Take on challenging (big) problems in an integrated manner (P4 medicine)

• New approaches to raising significant funds to attack big problems

• Integrate the efforts of the best in the world• Complementary technical and biological skills• Medical expertise and accessibility to patients,

patients samples and patient records• Exchange of talented scientists, engineers,

physicians and students

ISB Strategic Partnerships for P4 Medicine

• P4 Medical Institute (P4MI)—integrating selected companies and academics around P4 demonstration projects

• Bring systems biology, P4 medicine and biotech industry to Luxembourg

• Bring systems medicine to a US medical school

ISB/LuxembourgStrategic Partnership• Helping to creating a Center for System Biology similar to ISB

• Two collaborative research projects--$100 million over 5 years

• Helping establish biotech industry in Luxembourg—start ups and established companies--integrated personalized medicine company—Integrated Diagnostics

Two Luxemboug Research Projects

Tissue, Blood protein

And stem cell Read-out

Predictive, PersonalizedDiagnostics

ISB’s Approach to P4 Medicine: Genetics and Environment

integration is key to future medicine

Genome

Environment

Disease &

Health

Complex biological Networks

Systems Genetics

Luxembourg Strategy• Diseases of brain (neurodegenerative and cancer), liver

(toxicity, hepatitis C, fibrosis, cancer) and lung (cancer, fibrosis, COPD)

• Use mouse models for each—signal/noise and dynamical networks

• Genomes, transcriptomes, miRNAomes, proteomes, and phenomices—analyze patient disease organs, blood and differentiated disease-relevant tissues from iPS cells (individual patient stems cells)

• Develop relevant technologies, e.g. single cell. Individual genome analyses, etc.

• Integrate data into predictive networks

A Second Strategic ISB Partnership—the P4 Medical

Institute—ISB/OSU

Slide 61

Science & Technology

Policy & Industry

The P4 Medicine Institute

+

P4 Medicine Institute

A collaborative organization whose goal is to catalyze the personalized transformation of healthcare by:

• Accelerating translation of science to clinical practice• Developing public-private industry collaboration• Executing tangible & pragmatic demonstration projects• Addressing technical, strategic, operational, policy,

economic, & sociologic issues

P4MI Principles

1. Scientific innovation based upon systems biology and emerging technologies will yield “killer app” insights and innovations that will enable industry disruption

2. These technologic enablers will result in care that can be focused on health and wellness, the prediction and prevention of illness, individualized care for consumers of the future.

3. This disruption will provide a path to improved outcomes at lower costs via more effective diagnosis, more precise therapies, and reduced costs to bring therapies to market.

4. There exists current opportunities for insightful and visionary industry stakeholders to engage in business model redesign through participation in collaborative demonstration projects

Facilitating Opportunities

Science & Technology Policy & Industry

• Reorient care delivery systems to leverage new care models, consumer engagement, wellness-focused care

• Redesign incentives & reimbursement models to facilitate P4 Medicine

• Develop collaborative mechanism for involvement of the many & diverse stakeholders needed for the emergence of P4 Medicine

• Address regulatory requirements, legal protections, & policies needed to facilitate P4 Medicine

• Analyze sociologic, ethical, economic impacts associated with adoption of P4 Medicine

• Examine education requirements for medical workforce, industry, & consumers

• Develop methods to integrate genomic sequence data with diagnostic phenomic data

• Identify & characterize disease-specific biologic networks using systems approaches

• Identify & characterize organ-specific proteins, microRNA, other biomarker candidates

• Explore potential of novel technologies (in vivo molecular imaging, iPS cells, single cell analysis)

• Develop secure storage databases to manage complex & dense molecular & phenomic data

• Enhance EHR technologies to leverage novel content derived from molecular investigation

• Establish information management & governance policies for personalized datasets

Transformative & disruptive potential of P4 Medicine extends to the entire healthcare industry

Impact of P4 Medicine to Industry & Society

Science & Pharma

Health Systems & Payers

Patients & Consumers

Physicians & Education

Diagnostics & HCIT

Socioethical / Legal

• New dx tools that transform molecular data into content

• Electronic health records that leverage molecular data, correlate phenomic data, & provide true cognitive support

• Tech stack that integrates clinical, research, dx, & pt. generated data

• Rapid translation of science to clinical practice

• New drug discovery opportunities from systems biology

• Molecular blood ‘fingerprints’ to stratify disease & guide therapy selection

• Distribution of care locus – leveraging ‘medical home’ model

• Emphasis on wellness & prevention over illness

• Shift payer focus from volume to well-defined quality endpoints

• Preventive & predictive medicine yields new clinician thoughtflows

• Training must emphasize systems approach, HCIT support, risk & prediction, & personalization

• Privacy, security, consumer protection re: molecular data

• Consent for clinical & research use of molecular-level data

• Societal impacts of banked molecular data, biosamples

• Socioeconomic impact of P4 Medicine

• Personalization & Participation generate new consumer behaviors

• Consumer engagement technology requirements

• Consumer behaviors associated with biobanks & rapid scientific translation

P4MI Core Competencies

Translational Science

Social Sciences & Ethics

Policy & Regulation

TechnologyHigher

Education

Commercial Analysis

P4MI Charter Members

Healthcare Delivery Legal

Consumer Behavior

Slide 66

P4MI Charter Members (ISB/OSU)

Healthcare Providers

Patients & Consumers

Payors & Employers

Diagnostics & Biotech

Medical Education

Technology Vendors

Pharma & PBMs

Consumer Goods

Regulators & Foundations

3-5 Charter Members drawn from groups above

• Establish governance & business model• Collaborate on & commission projects of mutual interest• Provide early direction & prioritization• First rights to participate in projects of interest• Benefit from commercial potential & IP of derivative solutions

Science & Research

The Flattening of Many Worlds: Strategic Partnerships and the

Globalization of ScienceThe worlds of science, technology, health are flattening.

Tremendous opportunities for national and international strategic partnerships in science, technology and education.

• Network of interacting complementary, institutions

– Training in systems biology and recruiting the best world talent

• Transferring and collaborating on new technologies and computational tools

• Strategic partnerships on systems approaches to biology and P4 medicine

• New patient populations

• New fundraising and commercialization opportunities

The Opportunities and Challenges of P4 Medicine• Opportunities

– Explore mulii-billion dimensional data space leading to a deep understanding of disease mechanisms and hence effective and inexpensive new approaches to prediction, therapy ,prevention

– The potential to correlate 100s million of patient genotypes and phenotypes—and transform predictive medicine (diagnostics)

– Move rapidly towards a focus on wellness because of rapid responses to initial minor disease perturbations

• Challenges

– Data standaridized

– Universally accepted IT healthcare system to store, analyze, transmit, integrate and model data--no current system adequate

– Data available in an integrateable mode to analytic labs

– Biobanks for tissue and blood storage from individuals

– Ethics, social, legal, regulatory, economic issues resolved

– Deep research support for P4-oriented medicine to hasten its realization

The Conclusion• The current debate on healthcare is centered on

medicine of the past—and hence misses the enormous potential of medicine of the future (P4) for revolutionary change.

• Siloization with many different medical systems with different IT for healthcare, no data standardization, no effective biobanks for sample storage and no agreement on ethical, policy, societal, economic issues would be a disaster—integrative challenges

• Is the only the government in a position to handle the effective integrative challenges of P4 medicine?

The P4 Medical Institute Through the ISB/OSU Strategic Partnership

Could Play a Key Role in Accelerating the Emergence of P4

Medicine

Acknowledgements

Prion--Institute for Systems Biology

Daehee Hwang Inyoul LeeHyuntae Yoo

Eugene Yi (proteomics core facility)Bruz Marzolf (Affymetrix core facility)

Nanotechnology--J Heath, Caltech

Luxembourg projects--David Galas, ISB

P4 Medical Institute—Fred Lee, David Galas, Diane Isonaka

Prion--McLaughlin Research Institute Great Falls, Montana

Ranjit Giri Douglas Spicer Rajeev Kumar Rose Pitstick Rebecca Young

George A. Carlson