Stephen Albert Johnston, Salt Lake 53007

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Stephen Albert Johnston, Salt Lake 5/30/07
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Center for Innovations in Medicine
Proteomics, Diagnostics and Biodefense
NIAID Biodefense Proteomics Research Centers
4th Programatic Meeting
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Disruptive Innovation or Invention
Big Problem or Challenge in Biomedicine
Chemistry
Biology
Immunology
Computation
Solution?
Biodesign APPROACH to SCIENCE
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Biodesign Apollo Projects

• Tubes in the Desert Biofuels from
  Bugs
• Pathogen X Systematic Vaccine
  Production
• CanVac Prophylactic, Universal Cancer
  Vaccine
• DocInBox Presymptomatic Diagnosis of Disease

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Presymptomatic Diagnosis as Solution to
Healthcare Crisis
Big Problem Healthcare Crisis
Innovation Home-based Biosignature Diagnosis
Engineers Chemists
Immunologists Clinicians Mathematic
Modelers Computer Scientist
?Solution?
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Changing Spectrum of BioThreat Risk
Valley of the Shadow of Death
Decision Driven ?
Risk
Antibiotic Resistance
Natural Pathogens
Bio Revolution
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• Emerging Dual Technologies
• RNAi
• Cell Targeting
• Immunomodulation
• Genotype Pathogen Interactions
• Transformation/Engineering (neg.strd viruses,
  bacteria)
• -Chemical Synthesis of genes/life
• -New HTP screening systems
• -In vitro animals

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Sequence of all Microbes
Knowledge Of Host, Bugs And Disease Mechanisms
New Technologies
HTP Screening
Anything You Want
s.a.johnston, CIM
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Number of Variables Is Increasing
Nx df
Any combination of microbe and knowledge
N df
Anthrax Plague Smallpox Glanders etc
Select Agent Lists Scenario- Based Strategies
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Changing Spectrum of BioThreat Risk
Valley of the Shadow of Death
Decision Driven ?
Antibiotic Resistance
Natural Pathogens
Bio Revolution
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WHY THE WINDOW OF OPPORTUNITY?

• Soviet Program ended before the introduction of
  high end molecular biology
• Islam has viewed Biological Science as low
  science
• It is harder than you think the devil is in the
  details

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Platforms for Defense

• Fast Drug Production
• HTP Therapeutic Antibodies
• Platforms for Systematic Vaccine Production
• Chemical Vaccines
• Innate ImmunoProtection
• HOST BASED PRESYMPTOMATIC
• DIAGNOSIS

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DETECTION OF BIOATTACK OR OUTBREAK
RELEASE
PROGRESSION
Human
Disease SURVEILLANCE
SYNDROME
BioSense
ProMed
Bug
PATHOGEN in AIR
PATHOGEN in PEOPLE
BioWatch
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DETECTION OF BIOATTACK OR OUTBREAK
RELEASE
PROGRESSION
SYNDROME
Disease SURVEILLANCE
BioSense
ProMed
PATHOGEN in AIR
PATHOGEN in PEOPLE
PRE-SYMPTOMATIC HOST-BASED DETECTION
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Advantages of Host-BasedPre-Symptomatic Detection

• Treat to Prevent
• Containment of Outbreak
• Triage Based on Diagnosis
• Solution to AGENT X Problem
• DUAL USE TECHNOLOGY

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Biosignature Pattern Recognition in Human
Diseases Host-based Presymptomatic Detection of
Events
Genes Environment Age Sex
Serum/Cell components
State of Health
Center for Innovations in Medicine
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Personalized Medicine Based on Biosignatures
Continuous Monitoring of the Healthy
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Doc In Box BioSignatures
prognosis
Diagnostic Device
ILL
treatment strategy
diagnosis
Presymptomatic Diagnosis
NOT ILL
clinical validation
drugs/vaccines
Center for Innovations in Medicine
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Biomarkers versus BioSignatures
Biomarkers 47 clinically approved Biosignature
s 1000-1,000,000 elements
(proteins,peptides, metabolites, nucleic acids,
cells)
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Biosignatures vs Biomarkers Individual vs.
Population Normalization
Normal
Measure
Individual
T0 T1
Measure
Biosignature Elements
Center for Innovations in Medicine
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CRP
Cold
Normal Range
1
2
3 4 6
Assay
Days
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IDEAL Continuous monitoring of population for
BioSignatures to provide Presymptomatic
Detection Regardless of Pathogen (or Radiation
or Chemical)
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Specifications

• In house or frequently used places Well people
  have to use it.
• Inexpensive
• Thousands of measurements
• Robust, Near Real Time

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Upper Respiratory DiseaseIncubation Periods
5 Days
Sources http//www.emedicine.com/med/topic2339.ht
m http//virus.stanford.edu/adeno/adeno.html ht
tp//www.cdc.gov/flu/professionals/diagnosis/
1-4 Days
4 Days
7 Days
7-10 Days
5-8 Days
4-6 Weeks
Days
1 5 10
15 20
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Parameters for Biosignatures in Blood
Infection Site
nM
pM
x In Blood
fM
aM
?Blood
1h
12h
24h
36h
Time
BT R S 7 6 1023
Pri
T Viral Replication Time B Burst Size of
Infection R Amount of Protein Released Into
Blood S Stability of Protein in Blood Pr
Protein concentration in blood
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Pathogens on cells elicit gene expression patterns
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Specific pathogens elicit specific responses in
cells
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Journal of Virology, August 2001, p. 7059-7066,
Vol. 75, No. 150022-538X/01/04.000   DOI
10.1128/JVI.75.15.7059-7066.2001 DNA Microarray
Analysis of Chimpanzee Liver during Acute
Resolving Hepatitis C Virus Infection Catherine
B. Bigger,1 Kathleen M. Brasky,2 and Robert E.
Lanford1,
Detection of early responses to infection
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Cowpox Infection Model
Death Day 10
Symptoms Day 7
CPV
Mock
Blood drawn 3 Hours post infection
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Up at all time points
(colored by Venn Diagram)
(colored by expression
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Program to Create DocinBox Diagnosis
Human Studies
Animal Models
Instrumentation
DOCinBOX
Data Management
Signal Detection
Systems Biology
Computation Modeling
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Methods to Detect 1000s of Things Relevant to
Health

• RNA
• Established for 1000s
• Sensitive
• Sample Problems, Not Immediate Response
• Mass Spec
• Established for 1000s
• Post Modifications
• Sample Problems
• Antibodies
• Sensitive
• Robust
• Not 1000s

Problem Sample Preparation
Problem Production Of Antibodies
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New Types of Antibodies are Essential
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Basic Scheme
KD1
TARGET
Low Affinity Low Specificity Ligand 1
KD2
Low Affinity Low Specificity Ligand 2
Synbody KD KD1 KD2
Rigid Spacer Exact Distance
Tag, DNA, Fc
Effector Attachment Site
How to Make This Idea HTP??
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Synbody System
Leads
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4T 2016
2.2T 2007
Healthcare spending projections are based on the
2005 version of the National Healthcare
Expenditure data released by the Centers for
Medicare Medicaid Services (CMS) in January
2007. Source Centers for Medicare Medicaid
Services, Office of the Actuary, 2007.
Center for Innovations in Medicine
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18 of GNP on Health Care in 2006 Projected to
be 25 - 30 by 2015
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Average annual healthcare expenditures by age,
2005
Source U.S. Bureau of Labor Statistics, U.S.
Department of Labor. Consumer Expenditures in
2005. Report 998, Feb 2007.
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Total Population vs. 65 Population, 1950-2050
20.7 of the total population in 2050 is
estimated to be over 65 years old.
Only 8.1 of the total population in 1950 was
over 65 years old.
Source U.S. Bureau of the Census, multiple
Census years.
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What are the Costs of Medicine?
2.26T/Year Drugs Diagnostics Care
Estimated health expenditures for 2007
Source Centers for Medicare Medicaid Services,
Office of the Actuary, 2007. Healthcare spending
projections are based on the 2005 version of the
National Healthcare Expenditure data released by
the CMS in January 2007. Borger C, et al.
Health spending projections through 2015
changes on the horizon. Health Affairs.
March/April 2006 25(2) 61-73.
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The Cost of Post-symptomatic Medicine
Drugs 10
Diagnostics 2
Patient Care 88
2 Trillion in Direct Medical Costs per Year
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Two Options to Solve HC Crisis

• REDUCE CARE PROVIDED
• or
• TRANSITION TO PRE-SYMPTOMATIC DIAGNOSIS AND
  PREVENTATIVE MEDICINE

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Human Species Needs to Square Lifes Curve
Higher Quality Less Cost
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Convergence of Needs
Healthcare Crisis
PreSymptomatic Diagnosis
BioDefense
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The Lack of Effort in Host-Based, Pre-Symptomatic
Detection of Infection is the most CRITICAL
INVESTMENT NEED in our Biodefence Strategy
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Changing Spectrum of BioThreat Risk
Valley of the Shadow of Death
Decision Driven ?
Antibiotic Resistance
Natural Pathogens
Bio Revolution
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Medicine Art to Science
Sir William Osler 1892 If it were not for
the great variability among individuals,
medicine might be a science, not an art
Because of our new ability to measure variability
among individuals, medicine now can become a
science rather than an art.