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Biomedical Challenges at Skolkovo• What type of science will be done? What is leading-edge?• Systems medicine offers unique potential—for understanding
disease mechanisms, the need for intimate integration of diagnosis and therapy as well as new strategies for drug target discovery.
• Include non-profit (academic) as well as for profit? How can you enable company creation? How can you attract existing companies? What are appropriate non-profit models?
• Will you try and recruit back Russian scientists from abroad—or will you do it will resident Russian scientists?
• Will the Skolkovo money compete with that for other Russia sciences (or the National Academy)? If so, expect resistance.
• Will you employ strategic partnerships to jump start the creation of Skolkovo? If so, resources will have to go to strategic partners.
• Will you reform your current academic science in keeping with the bold Skolkovo initiative? Two keys: give young scientists an opportunity and resources to direct their own science at an early age and realize the essential nature of good peer review in the allocation of science resources.
Systems Biology and Systems
Medicine: Leading-Edge Science and
Technology, Healthcare, Strategic
Partnerships and Commercialization
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.
The Grand Challenge of the 21st Century in
Science and Technology Is Complexity
• New concepts, strategies and technologies permit biologists to successfully begin to attack biological complexity
– View biology as an informational science– Systems approaches permit one to attack complexity
effectively– Evolving current and emerging technologies permit the
exploration of new areas of data space (and improve the old)
– Computation and mathematical tools permit one to acquire, store, transmit, integrate, mine and create predictive models.
• These approaches will allow us to effectively attack some of society’s most vexing challenges—healthcare (P4 medicine), global health, environment, energy, nutrition, agriculture, etc.
The Foundations of Systems Biology and
Systems Medicine – Four Pillars
1. View medicine as an informational science
2. Systems approaches allow one to understand wellness and disease—holist rather than atomistic
3. Emerging technologies will allow us to explore new dimensions of patient data space
4. Transforming analytic tools will allow us to decipher the billions of data points for the individual--sculpting in exquisite detail wellness and disease
• The digital information of the genome
Human Phenotypes are Specified by Two Types of Biological Information
• Theenvironmental information that impinges upon and modifies the digital information
Two General Biological Structures Connect
the Genotype/Environment and Phenotype
• Biological networks capture, transmit, process and pass on information
• Simple and complex molecular machines execute biological functions
DNA
RNA
Protein
Protein interactions and biomodules
Protein and gene networks
Cells
Organs
Individuals
Populations
Ecologies
All Hierarchical or MultiscaleLevels of Biological
Information—Are Modified by Environmental
Signals
The Foundations of Systems Biology and
Systems Medicine–Four Pillars
1. View medicine as an informational science
2. Systems approaches allow one to understand wellness and disease—holist rather than atomistic (systems biology and systems medicine)
3. Emerging technologies will allow us to explore new dimensions of patient data space
4. Transforming analytic tools will allow us to decipher the billions of data points for the individual--sculpting in exquisite detail wellness and disease
Agenda: Use biology to drive technology and computation. Need to create a cross-disciplinary culture.
COMPUTATION TECHNOLOGY
BIOLOGY
Biological Information
Cross-DisciplinaryCulture
Team ScienceTraining
• Biology
• Chemistry
• Computer Science
• Engineering
• Mathematics
• Physics
Essentials of Systems Biology
• Create model from extant data—formulate hypotheses to test model through experimental perturbations of system--hypothesis-driven and hypothesis-generating
• Data– Global data acquisition– Integrate multi scale data types– Delineate biological network dynamics—temporal and
spatial– Dealing with biological noise and technical noise in large
data sets
• Formulate models that are predictive and actionable—descriptive, graphical or mathematical.
• Discovery science is key
ISB’s description of systems biologyin 2000 is virtually identical to that ofthis National Academy of Sciences 2010 report entitled the “New Biology”.
ISB was the first Systems Biology organization in 2000—today there are more than 70 world wide
Report predicted that systems approaches would drive biology and medicine of the future
ISB
CNRS
Chinese Academy of Science
Russian Academy of Sciences
SangerInst. Nat. dePhysique Nucleaire
CSHLSSM Cardinal GlennonChildren’s Hospital
RockefellerMIT
WHO HHMI
Salk
MSFTHarvard
FHCRC
Brigham andWomen’s Hospital
IBM
Harbin EngineeringUniversity
TianjinUniversity
National Academy ofSciences of Ukraine
Research Institute ofPetroleum Processing
ParcMediterranide laTecnología
Centro deInvestigaciónPríncipeFelipe
Institut Catalad’InvestigacioQuimica
International Agency forResearch on Cancer Kaiser Permanente
ISB 1st in US and 3rd in World for Impact of Papers
SCImago Institutions Rankings: http://www.scimagoir.com/
A Systems View of Medicine Postulates that Disease Arises from Disease-Perturbed Networks
Non-Diseased Diseased
dynamics ofpathophysiology
diagnosis
therapy
prevention
A Systems Approach to a
Neurodegenerative Disease (prion
disease) in Mice
• Do the disease-perturbed networks in brain cells explain the pathophysiology of prion disease? Yes
Global and Subtractive Brain Transcriptome Analysis—
Differentially Expressed Genes (DEGs)
Uninfected brain
Prion infected brain
Inoculate w/ Prions
Time-course array analysis:subtrative analyses to DEGs
Mouse Genome array:45,000 probe sets
~22,000 mouse genes.
RNA
from brain
homogenate
Prion strains:• RML• 301V
Mouse strains: C57BL/6J FVB/NCrBL6.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
7400 DEGs to 333DEGs—signal to noise issues---biological/technical
Neuropathology Identifies 4 Networks
PrP accumulation Microglia / Astrocyteactivation
Synaptic Degeneration
Normal Infected
Nerve cell death
Prionaccumulation
GlialActivation
SynapticDegeneration
Neuronal Cell Death
Cholesteroltransport
Sphingolipidsynthesis
Lysosomeproteolysis
ReactiveAstrocytes
Leukocyteextravasation
Na+
channels
Cargotransport
Caspases
*Arachidonatemetab./Ca+ sig.
Clinical Signs
Sequential Disease-Perturbation of the Four Networks of Prion Disease
0 wk 18~20 wk 22 wk
Making Blood A Window Distinguishing
Health and DiseaseOrgan-specific Blood Proteins
Blood Vessel
110 brain-specific blood proteins/80 liver-specific blood proteins
Why Systems-Driven Blood Diagnostics Will Be
the Key to P4 Medicine
• Early detection
• Disease stratification
• Disease progression
• Follow therapy
• Assess reoccurances
Integrated Diagnostics
Disease Stratification – HerceptinWhy Diagnosis/Therapy Must Be Integrated
50% reduced risk of recurrenceafter one year
Some women with metastatic breast cancer have
tumors that overexpress the HER2 gene and
have a poorer response to chemotherapy
Identifying HER2+ patients with genetic
(FISH) or immunological (IHC) tests and
targeting with Herceptin improves treatment.
Herceptin +
Target treatment…
HercepTest®
Pathway®
PathVysion®
HER2 pharmDx™
IHC
FISH
The Foundations of Systems Biology and
Systems Medicine–Four Pillars
1. View medicine as an informational science
2. Systems approaches allow one to understand wellness and disease—holist rather than atomistic
3. Emerging technologies will allow us to explore new dimensions of patient data space
4. Transforming analytic tools will allow us to decipher the billions of data points for the individual--sculpting in exquisite detail wellness and disease
Big Science/Small Science
• Two types of big science– Discovery (human genome project)– Integrative, cross-disciplinary, hypothesis driven, focused
on concrete objective
• Small science—individual investigator initiated
Big and small science are synergist—and should be integrated
Currently an enormous conflict at the NIH funding levels for big science. Should have a balanced portfolio of big and small science.
Four ISB Technology-Driven New
Big Projects
• Complete genome sequencing of families—sequences and new stratifications to identify disease genes—1000s individuals
• The Human Proteome Project—SRM mass spectrometry assays for all human proteins
• Clinical assays for patients that allow new dimensions of data space to be explored
• The 2nd Human Genome Project—mining all complete human genomes and their phenotypic/clinical data
Whole Genome Sequencing of
Families: A New Genomic Strategy
• Sequencing by Complete Genomics, Inc.
• D. Galas, J. Roach, G. Glusman and A. Smit at ISB
• Collaboration with human geneticists at the UW and Utah
Whole Genome Sequencing of Family of Four
Unaffected parents
Children each with 2 diseases--craniofacialmalformation (Miller Syndrome) and lung disease (ciliarydyskinesia)
Identify 70% of sequence errors using principles of Mendelian genetics—less than 1/100,000 error rate—now 1/ 1,000,000Discovery of about 230,000 rare variants in family—confirmed by identificationin two or more family members
Reduce the genome haplotype search space for disease genes—Mendelianhaplotype blocks reduce space to ¼ haplotypes for each individual
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X
centromere
error region
heterochromatin
haploidentical maternal
identical
haploidentical paternal
nonidentical
CNV
candidate gene
maternal recombination
paternal recombination
DH
OD
HK
IAA
05
56DN
AH
5
ZNF7
21
Miller’s gene
Ciliarydyskenesis gene
Genomes of kids
Sibling genomes are identical across ~25% of their length
(23.2% here)
Family Genome Sequencing May
Facilitate Finding
• Mendeliandisease genes
• Modifiers of disease genes--sequencing genomes of about 80 Huntington’s patients from families—mostly finished
• Genes encoding complex genetic diseases after proper patient stratification—Alzheimer’s/Parkinson’s diseases
Game Changer—
declining cost of sequencing genomes will make them a part of your
medical record in 10 years or less
The Human Proteome Project
• Strategic partners: ISB (R. Moritz)/ETH (R. Aebersold)/Agilent/AB-Sciex/Origene
2. TPP: Foundation for PeptideAtlas
Advanced, uniform processing of all data
Drives tool development and optimization
38
3. Targeted Proteomics: Human SRMAtlas
4. SRM assays for most of the known 20,333
human proteins
Analyze 100-200 proteins quantitatively in 1 hour
Making Blood a Window into Health and Disease for 100s millions of patients:
50 organ-specific blood proteins from each of 50 organs
Integrated nanotech/microfluidics platform
Jim Heath, et al
cells out
300 nanoliters of plasma
Assay region
5 minute measurement1. Uses fraction of droplet of blood2. Assay takes 5 minutes3. Dynamic range 106
4. Potential for thousands of protein assays on one chip
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
allergies– 200 Actionable SNPs—pharmacogenetics-related and disease-related genes– Sequence 1000 transcriptomes—tissues and single cells—stratification disease– Analyze aging transcriptome profiles—tissues and single cells—wellness– Analyze miRNA profiles—tissues, single cells and blood—disease diagnosis
• Proteomics– Organ-specific blood MRM protein assays—110 brain, 80 liver and 20 lung
– 2500 blood organ-specific blood proteins from 300 nanoliters of blood in 5 minutes—twice per year (50 proteins from 50 organs)—wellness assessment.
– New protein capture agents.– Array of 13,000 human proteins—against autoimmune or allergic sera--stratify.– Single molecule protein analyses—blood organ-specific proteins and single cell
analyses
Individual Patient Information-Based Assays of
the Present/ Future (II)
• Single cells• Analyze10,000 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 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.
Induced Pluripotent Stem Cells
Blood draw or skin biopsy
Induced pluripotent stem (iPS) Cells
Introduce four reprogramming factors
Induced Pluripotential Stem Cells (iPS cells)
Induced Pluripotent Stem CellsTwo Critical Characteristics
Replicate Indefinitely Make all
100s or more cell types in human body
Induced Pluripotent Stem (iPS) Cells
What’s so special about iPS cells?
The Foundation of Systems Biology and Systems
Medicine–Four Pillars
1. View medicine as an informational science
2. Systems approaches allow one to understand wellness and disease—holist rather than atomistic
3. Emerging technologies will allow us to explore new dimensions of patient data space
4. Transforming analytic tools will allow us to decipher the billions of data points for the individual--sculpting in exquisite detail wellness and disease
In 10 years a Virtual Cloud of Billions of Data Points Will
Surround Each Individual
Transactional
110101000101010101101010101001000101101010001
Phenome
Na143 K 3.7 BP 110/70
HCT32 BUN 12.9 Pulse
110 PLT150 WBC 92
GCGTAGATGCGTAGGCATGCATGCCATTATAGCTTCCA
Genome
Proteome
arg-his-pro-gly-leu-ser-thr-ala-trp-tyr-val-met-phe-asp-cys
Transcriptome
UUAGUGAUGCGUCUAGGCAUGC
AUGCC
Epigenome
110101000101010101101010101001000101101010001
Single Cell
110101000101010101101010101001000101101010001
iPS Cells
110101000101010101101010101001000101101010001
Social Media
110101000101010101101010101001000101101010001
TeleHealth
110101000101010101101010101001000101101010001
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
49
ISB Strategic Partnerships:
Objectives
• Critical to fulfill ISB’s mission of attacking big scientific problems
• Complementary scientific/medical expertise
• New funding resources
• Assess to new patient materials and records
• Access to novel technologies and analytic tools
• Gather the best scientists in the world to do big science—integrative, cross-disciplinary, hypothesis-driven science.
ISB’s Strategic Partners for P4
Medicine
• Develop the P4 tools and strategies for patient assays—State of Luxembourg--$100 million over 5 years
• Bring P4 medicine to patients with the creation of the non-profit P4 Medical Institute (P4MI) in partnership with Ohio State Medical School—two pilot projects—wellness and heart failure
ISB/Luxembourg
Strategic Partnership
• Helping to creating a Center for Systembiomedicine similar to ISB—Rudi Balling Director—recruit and training of personnel
• Helping establish biotech industry in Luxembourg—start ups and established companies--integrated personalized medicine company—Integrated Diagnostics
• Two collaborative research projects--$100 million to ISB over 5 years
The P4 Medicine Institute (http://www.P4MI.org)
• Non-profit 501c3--ISB and Ohio State founding members• Vision--identify, recruit and integrate strategic partners
with ISB to bring P4 medicine to patients—create a small network of large and small medical centers
• Convince a skeptical medical community through demonstration with two Ohio pilot projects (and others)—wellness and heart failure—exhibit success and power of P4 medicine
• Seek academic and industrial partners who share the P4 vision and have complementary skills/resources
• Bringing on consultants to analyze the societal challenges of P4 medicine—ethics, security, confidentiality, policy, regulation, economics, etc.
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
13 Companies Founded Or Cofounded
By Hood Lab: Transferring Knowledge to
Society
• Applied Biosystems--molecular instrumentation--technology• Amgen--molecular biology--biology• Systemix--stem cell biology--biology• T Cell Sciences--T cell therapies--biology• Darwin--genomics--technology• Prolinx--protein chemistry--technology*• Rosetta--global array analyses—technology• Geospezia—informatics• Cytopeia—high speed, multiparameter cell sorting• Macrogenics--antibodies and innate immunity—biology• Nanostring--digital counting of RNA molecules--technology• Accelerator--commercialize early start-ups--business• Integrated Diagnostics--blood diagnostics--medicine
ISB’s Accelerator Corporation
Accelerator Corporation1616 Eastlake Avenue East
Carl Weissman CEOSeattle
For Profit Company:•Commercializing cutting edge ideas in Systems Biology and related fields--6 new companies founded--more than 350
business plans reviewed
•ISB to get founders equity--long term endowment--facultyconsulting and facilities access
Established: May, 2003
Partners:ISB + 6 Life Science Leaders
CEO: Carl Weissman
Location: Seattle – 10 minute drive from ISB
•Arch Ventures ($1 B+)•MPM Capital ($2.1 B)•Versant ($650 M+)•OVP ($500)•Amgen ($100)•Alexandria Real Estate Investment Corp
Essential Components for Starting
Companies• A good scientific idea that creates a marketable product• Clear business plan that is milestone driven• Good management—the CEO is critical• Capital—with staying power if the company is successful—in biotech
company development is expensive and takes time• Those who can critically evaluate startups—and can select the 1/100
successful companies—this is critical• Skilled workforce—good young scientists• A clearly formulated one or more provisional exit strategies• Entrepreneurial scientists—with an inclination to think about how their
science can be transferred to society—how do we train?• Fostering serial entrepreneurs• A source of good science for company ideas—usually outstanding
academic centers• Intellectual property is key• National and international opportunities for funding
Conceptual Themes of P4 Medicine
Disease DemystifiedWellness Quantified
P4 MedicinePredictive
Preventive
Personalized
Participatory
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, single organs and single individuals
• I Phone-like device with digitalize personal records—monitoring and access
• 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 Is 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., ability to attack big problems such as P4 medicine
• Technology development
• Pioneer computational tools
• Transferring knowledge to society-creating companies--changing K-education
• Strategic partnerships—for bigscientific problems—e.g. P4
medicine--industrial, academic, government, international
Biomedical Challenges at Skolkovo
• What type of science will be done? What is leading-edge?• Systems medicine offers unique potential—for understanding
disease mechanisms, the need for intimate integration of diagnosis and therapy as well as new strategies for drug target discovery.
• Include non-profit (academic) as well as for profit? How can you enable company creation? How can you attract existing companies? What are appropriate non-profit models?
• Will you try and recruit back Russian scientists from abroad—or will you do it will resident Russian scientists?
• Will the Skolkovo money compete with that for other Russia sciences (or the National Academy)? If so, expect resistance.
• Will you employ strategic partnerships to jump start the creation of Skolkovo? If so, resources will have to go to strategic partners.
• Will you reform your current academic science in keeping with the bold Skolkovo initiative? Two keys: give young scientists an opportunity and resources to direct their own science at an early age and realize the essential nature of good peer review in the allocation of science resources.