Center for Innovations
in Medicine
Towards a World Without
Patients
TRILOGY STEMS Group
February 3, 2012
Stephen Albert Johnston
Center for Innovations in Medicine
Biodesign Institute
Stephen.johnston@asu.edu
1
DISCLOSURE
Relevant Financial Relationship(s)
HealthTell, Inc
Calviri, LLC
An Alternative Approach to Academic Science
Traditional Approach
CIM Approach
Scientist’s area of expertise
drives the research focus
Societal needs drive the
research focus—then the
needed experts are tapped
Research addresses highly
specific component of a
problem– may later be
stitched to other
components.
A team addresses the
identified need in an
orchestrated manner,
linking the components
(project management)
Applications—if pursued—
emerge from the findings
The area of application is
clear throughout project;
may be adapted by the
findings.
Big Problem or
Challenge in
Biomedicine
Biology
Solution?
Disruptive
Innovation
or Invention
Chemistry
Immunology
Computation
CIM’s APPROACH to SCIENCE
CIM: Focus on TRANSFORMATIVE Technologies
Blue Ocean Strategy by W. Chan Kim and Renee Mauborgne, 2005
Apollo Projects in Healthcare
• 1. Universal, Preventative Cancer Vaccine
• 2. Inexpensive, Comprehensive Health
Monitoring System for Early Diagnosis of Any
Disease.
• 3. Synbodies: Solution to Antibiotic Problem
Forbes Magazine, 1/19/2012
U.S. Healthcare Hits $3 Trillion
National Healthcare Expenditure – or NHE.
… NHE for 2012 is probably closer to $2.7 trillion but there’s this nagging bookkeeping
accrual of about $300 billion where we (narrowly) avoided those darn pesky SGR cuts
to Medicare. … That puts the real NHE at about $3 trillion for 2012 (+ about 4% for
As one economist
said – we don’t have a debt problem in this
country – we have a healthcare problem.
each year forward – as far as the eye can see).
http://www.forbes.com/sites/danmunro/2012/01/19/u-s-healthcare-hits-3-trillion/
$3 trillion is ~19% of the GDP for the US
7
Healthcare:
Systems management vs. crisis management
A process engineer at a chemical manufacturing plant would not wait
until this happened before intervening. Why do we?
We need both different tools and different thinking to apply
process control principles to medicine.
8
How to Frighten a 20-year Old
Me
You
http://flatrock.org.nz/topics/money_politics_law/boom_moves_along.htm
Post-Symptomatic Medicine
To Pre-Symptomatic Health
2009 GNP $14.7T
2009 Health Care Costs $2.5T
Per capita health expenditure ~$8000
Median adjusted gross income in 2007 ~$33,000*
Median federal taxes per capita in 2007 ~$1,000
Total Medicare expenditures in 2004 ~$3B
Medicare expenditure per capita ~$1000
Graphs from “Trends in Health Care Costs and Spening, Kaiser Family Foundation, March 2009
http://www.kff.org/insurance/upload/7692_02.pdf; *gross income and tax data from the Tax Foundation
http://www.taxfoundation.org/news/show/250.html
Transition from Post- to Pre-Symptomatic Medicine
Requires System to Continuously Monitor Health of
Well People
Specifications:
-Comprehensive
-Sensitive – Early Detection
-Simple
-Inexpensive
-Specificity – What is Wrong?
Breast Tumor Evolution
Detection Method
Number of
doublings
0
10
20
30
40
Number of
tumor cells
0
103
106
109
1012
Volume of
tumor
0
.000001
ml
.001 ml
1 ml
1,000 ml
Weight of
tumor
0
1 microgm
1 milligm
1 gm
1 Kg
Clinically
Detectable
(27)
Angiogenesis
/metastasis
Oncogenic
Signaling
Kim Lyerly, Duke University
(1-2mm3)
Mammogram
“Circulating”
biomarkers
Molecular
Breast
Imaging
Can Not Do Early Detection of Disease
Blood Dilution Problem
104 Improvement in Detection
Needed
Sci Transl Med 3, 109ra116 (2011);
Sharon S. Hori, et al.
Detection Strategies and Limitations
Mathematical Model Identifies
Blood Biomarker-Based Early Cancer
The Immune System Detects and Amplifies Signal
• 108 to 109 antibodies exist in serum
• A single reactive B cell encounters
antigen and is activated
• Produces 5,000 to 20,000 antibodies
per minute
• Divides every 70 hours
• Signal is amplified ~1011 times in one
week
Center for Innovations
in Medicine
sample
ImmunoSignature Assay
Components
dilute
apply
•
•
•
•
Facile sampling of easily obtained
blood/saliva
No sample prep other than dilution
Potential for broad, specific pathogen
detection
Samples stable dry on filter paper for
weeks
monitor
15
Center for Innovations
in Medicine
Immunosignature Process
Array of 10K-330K,
Addressable
Random Sequence Peptides
16
Center for Innovations
in Medicine
Immunosignature Process
Add diluted blood
17
Immunosignature Process
Wash
18
Immunosignature Process
• One array for all
samples, human and
nonhuman
• Very small quantity of
blood required
• Scalability and low
cost array fabrication
Wash
19
Nature Does Not Always Know Best
- Life occupies an infinitesimally small part of potential sequence
space
- Therefore there are many other sequences that could be useful
- Peptides on array chosen to evenly sample random sequence space
(3.5x105/ 1021 possibilities)
Consequences: Same set of peptides can be used for
any diagnosis
Super-fine resolution of antibody diversity
Features of Immunosignatures
Same chip used for all diseases, all species
Detects all antibodies: sugars, non-linear, modifications
Historical sera samples work
No sample preparation
10-100x more sensitive than Elisa
Center for Innovation
in Medicine
Immunosignature Patterns from Various
Monoclonal Antibodies
22
Classic Train/Test Example:
Valley Fever
Normal
• 10,000 peptides on original array
• 120 patients screened and analyzed
• 100 most informative peptides
selected and resynthesized
• Diagnostic array printed
Infected
John Galgiani
Univ. of Arizona
23
Outperforms Existing Diagnostic
Patients with Valley Fever
Patients that did not have Valley Fever
• 90 blinded samples from patients presenting at the clinic
• Zero false positives (100% specificity)
• Zero false negatives (100% sensitivity)
All Patients with Valley Fever Presented with Zero CF Titers, but were later
shown to have the disease
24
Immunosignaturing Brain Tumors
Collaborator: Adrienne C. Scheck, BNI
100% accurate
detection training and
testing on samples
taken years apart
using printed arrays
Not only can
immunosignaturing
detect the brain
tumor, it can
distinguish
accurately between
the common types of
brain tumors
25
Alzheimer’s:
Alzheimer’s Disease Neuroimaging Initiative (10K)
Alzheimer’s Disease
Controls
Disease: ADNI collection of serum samples from Alzheimer’s Disease (AD) and non-AD
controls
Feature selection: 1 sided T-test, 50 peptides were selected
Classification: 4 samples were called normal when they were Alzheimer’s (FN)
Sensitivity=89%, NPV=92%, Accuracy=95%, specificity and PPV=100%
Interpretation: AD signature blends gradually into controls with no clearly defined
threshold
Towards Comprehensive Testing
Ovarian
MM
Pancreatitis
Healthy controls
BC stage 2, 3
15 Diseases Simultaneously Analyzed
Mixed GBM Astrocytoma
Oligo/Astro
27
Sarcoma
Lung
BC stage 4
Pancreatic
Oligodendroglioma
Breast Valley Fever
2nd tumor
Cross Validation, 15 Diseases
28
Transition from Post- to Pre-Symptomatic Medicine
Requires System to Continuously Monitor Health of
Well People
Specifications:
-Comprehensive
-Sensitive – Early Detection
-Simple
-Inexpensive
-Specificity – What is Wrong?
30
Vision: Eradicating Cancer by Immunosignature Monitoring of
With current diagnosis
and treatment, the
cancer death will be
585,720 in 2014.
detected by image or
symptoms start the treatment
Anti-CTLA4
Anti-PD-1
chemotherapy
Earlier
diagnosis
treatment,
higher survival
detected by IMS closely monitor by IMS Cancer is
start the treatment evacuate the treatment eradicated
Platform 1: Printed Arrays of 10,000
Peptides
17 amino acids long, random sequence, and all amino acids except C are
used. Two copies of the library are printed on a glass slide (~1200
peptides/cm2).
Mass spectra available for all peptides spotted on the arrays.
32
Making it Inexpensive & Scalable:
In situ synthesized peptide arrays
• Scalable production
• Low cost at high volume
• Utilizes decades of
fabrication technology
development
• Integrates with Electronics
33
33
•
•
•
Standard fabrication instruments
8 micron features (high density)
312 assays per wafer
High density  High information content  High volume  Low cost
34
34
Visualizing Features
330,000 peptides were
synthesized in a 0.5 cm2
region (8 micron
features, 13 microns on
center). Binding of a
monoclonal antibody to
so many sequences
give a broad dynamic
range of signal (about
300:1).
35
330K Arrays: Simultaneous Discrimination
of 7 Infectious Diseases
127 blood samples
from 7 diseases, 2
WNV miss-classified
as normal
The 330K synthesized arrays do an excellent job of distinguishing multiple dise
36
Discriminating Four Cancers with the
330K Arrays
Breast
Esophogeal
Glioblastoma
Ovarian
37
Gates Foundation Vaccine Grants
Disease
Deaths (millions/year)
Grants for Vaccines
($millions)
Acute Diarrheal Illness (ADI)
2-3
$72.
Acute Lower Respiratory Infections
(ALRI)
2
$139
HIV/AIDS
2.8
$421
Malaria
1
$425
Tuberculosis
1.6
$107
Vaccine-Preventable Diseases
2
$66
Other Infectious Diseases
?
$183
Cancer
5
$0.0
Apollo Projects in Healthcare
• 1. Universal, Preventative Cancer Vaccine
• 2. Inexpensive, Comprehensive Health
Monitoring System for Early Diagnosis of Any
Disease.
• 3. Synbodies: Solution to Antibiotic Problem
Problem
• Cancer kills ~8M people each year
• ~70% of deaths are in developing world
• Cost is >$1T worldwide, >1.5% of GDP
• Solutions being advanced (eg proton
emission treatment, personal therapeutics)
are only cures, expensive and unimaginative
Cancer Treatment Costs Too Much
for Use in Developing World
• Breast cancer drug Herceptin: ~ $30,000 a year
• Colorectal, lung and breast cancer drug Avastin:
~ $50,000 a year
Contribution of Cancer to HC Costs
$250B Direct
Cancer Costs
$2.4T Total Costs
= 10% of
Total HC
Costs
Anne Weston, picture of “How to Cure Cancer”, Time magazine web, June,2013
Solution
• Develop a preventative vaccine for all cancers
• Solves problems inherent in treating tumors
• Inexpensive, accessible to whole world
• Simple and Revolutionary
The Problem with Therapeutic Cancer Vaccines
Aberrant tumor proteins
infection
vaccine
Foreign Antigen
+
DANGER
Foreign Antigen
NO
DANGER
TOLERANCE
Strong Immune Response
Suppression of immune
response to tumor
antigens
Willimsky, G. and T. Blankenstein. 2005. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance.Nature 437:141-146
8
1
8
2
6
5
2
6
4
8
3
7
3
7
1
5
4
1
9
2
14
3
7
6
5
13
NO Protection
Protection
9
A
14
13
Protection ?
C
10
11
8
8
11
8
4
12
B
10
12
Strategy
• Find neo-antigens that occur in >5% of all
tumors
• Pool enough neo-antigens (~10-20) to
anticipate presentation by any new tumor
• Vaccinate before tumor presents neoantigens
The Challenge: Find Enough Tumor Specific
Antigens in Common
Tumors
2
1
3
4
200
Tumor
Specific
Antigens
VACCINE =
+
+
+
Any Tumor Arising Would
Have 100% Chance of Presenting
One or More Antigens
Background
smc1a Frame Shift Splicing
Wild Type smc1a
Frame Shift smc1a
Frame-Shift transcript of smc1a is caused by alternative splicing exon1 to exon 4.
The splicing causes reading frame shift of exon4 and generates a 17 amino acids
long FS peptide.
BALB-NeuT tumor progression curve
% tumor number <10
100
75
50
25
0
0 5 15
25
35
Age (week)
Control
Individual
3Ags pool
Fig: The tumor inhibition of FS antigens in BALB-NeuT mouse breast tumor
model. Control vs individual antigen or pool antigens p<0.0001; Individual
antigen vs. pool antigens p<0.005
Red labled Median normalized value >10; sorted by sample types,
the same color code, white is normal sample. 345 peptide have at least 1 sample >10
5.00
4.50
4.00
3.00
2.50
2.00
1.50
1.00
0.50
Positive rate of one peptide of ODZ4-NRG in normal and breast cancer samples.
Normal: 3.2%; Breast cancer: 54.7%
BC92
BC87
BC77
BC82
BC72
BC67
BC62
BC57
BC47
BC52
BC42
BC37
BC32
BC27
BC22
BC12
BC17
BC7
BC2
N91
N86
N76
N81
N71
N66
N61
N56
N46
N51
N41
N36
N31
N26
N16
N21
N11
N6
0.00
N1
Normalized signal value
3.50
Phase II Trial Design
IMS
Cancer Event
Cancer Prevent Event
IMS
Vaccine Group
Cancer Free
Volunteer
No Cancer Event
Cancer Event
Control Group
No Cancer Event
Solution to Conducting Phase II
Efficacy Trial in Humans:
DOGS
36% Lifetime Risk of Cancer
$5M to Conduct Trial
Use Immunosignatures to Shorten Trial, Decrease Cost
Fast to Market
$100M/yr Sales in USA
If It Works for Dogs – Will Likely Work for People
Company: Calviri, LLC
(A) Proton Emission
(B) Preventative
Cancer Vaccine
Development:
$200B (1000 ctns)
$1B (Phase III)
Cost/Year:
$50B
$1B ($100/shot)
Cost/Trtment
~$30,000
$100
Physicists
10,000
0
Plan A or B?
Source: Mayo web site, http://www.npr.org/blogs/health/2012/10/29/163635298/
Acknowledgements
•
Innovations In Medicine
– Neal Woodbury, co-director
– Chris Diehnelt
– John Lainson
– Zbigniew Cichacz
– Phillip Stafford
– Zhan-Gong Zhao
– Donnie Shepard
– Bart Legutki
– Andrey Loskutov
– Penny Gwynne
– Loren Howell
– Douglas Daniel
– Rebecca Halperin
– Lucas Restrepo
– Luhui Shen
– Hu Duan
– Debra Hansen
– Pattie Madjidi
•
•
•
•
$Funding: The Biodesign Institute at ASU
HealthTell, Inc.
DTRA, NSF, DARPA, ARO
HealthTell, Inc.
– Bill Colston
– Kathryn Sykes
– David Smith
– Fabrication Team
NextVal, Inc.
– Matthew Greving
Complex Adaptive Systems Initiative
– George Poste
Other Collaborators
– John Galgiani, U. of Arizona
– Hoda Anton-Culver, UC Irvine
– Sam Hanash, Fred Hutchinson Cancer Center
– Adi Gazdar, UT Southwestern
– Adrienne Scheck, Mayo Clinic
– Dawn E. Jaroszewki, Mayo Clinic
57