Medicine of the Future—The Transformation from Reactive to Proactive (P4) Medicine
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Transcript of Medicine of the Future—The Transformation from Reactive to Proactive (P4) Medicine
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
confidential 36
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
43
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