Dr. Mildred A. DonlonProgram Manager,Defense Advanced Research Projects AgencyDefense Sciences Office3701 North Fairfax DriveArlington, VA [email protected]
http://www.darpa.mil/dso
All slides have been cleared for public release
22
Director, Tony Tether
Defense SciencesMichael Goldblatt
Steven Wax
Bio Warfare Defense TechnologiesBiologyMaterials & DevicesMathematics
Information ProcessingRonald BrachmanZachary Lemnios
Architectures & DesignsComputer Processing & StorageNetworks Human Computing
Interfaces
MicrosystemsTechnologyRobert Leheny
John Zolper
ElectronicsOptoelectronicsMEMSCombined
Microsystems
Tactical TechnologyAllen Adler Art Morrish
Air/Space/Land PlatformsUnmanned SystemsSpace OperationsLaser SystemsFuture Combat SystemsPlanning / Logistics
Advanced TechnologyDavid HoneyLarry Stotts
Assured C3ISRMaritimeEarly Entry/Special Forces
Special ProjectsAmy AlvingJoe Guerci
Chem/Bio Def SystemsCounter Underground FacilitiesSpace Sensors/StructuresNavigation/Sensors/ Signal Processing
Information ExploitationStephen WelbyRobert Tenney
Sensors
Exploitation Systems
Command & Control
Information AwarenessJohn Poindexter
Robert Popp
Asymmetric Threat
Prediction
Behavior Modeling
DARPA OrganizationDARPA Organization
33
DARPA AccomplishmentsDARPA Accomplishments
Taurus LaunchVehicle
Global Hawk
MALD
Predator
MEMSTMR
Uncooled IR
BAT
JSF
19901990
UCAV
20002000
Vela HotelSaturn
M-16 Rifle
GroundSurveillance Radar
JSTARS
ATACMS
19601960
19701970
ArpanetStealth Fighter
Sea Shadow
19801980
GPS
44
Harvesting Biology for Revolutionary Technologies at DARPA
Harvesting Biology for Revolutionary Technologies at DARPA
EnhancedHuman Performance�Making People More Than They Can Be�
Biocomputation
New Materials
Genomics &
proteomics
The bio-silico interface
Brain Technology
Bioinformatics
Behavior
Energy Transduction
Infrastructure
Enhanced System Performance
�Using Biology to Enhance
Defense Systems�
Protecting Human Assets
�Defending against
Biological threats�
55
Biology is a major driver for new math and physics
Biology is a major driver for new math and physics
• Interrogate and manipulate biological systems with modern physical devices
• Analyze, model, simulate & design with a new arsenal of math and computational tools
10 nmout
in
+++ ++
+
77
88
NEAR MID FAR
Scie
nce
& T
echn
olog
y $
Service S&T
Fundamental Research
DARPA Role in Science and TechnologyDARPA Role in Science and Technology
99
NEAR MID FAR
Scie
nce
& T
echn
olog
y $
Service S&T
Fundamental Research
DARPA
DARPA Role in Science and TechnologyDARPA Role in Science and Technology
1010
NEAR MID FAR
DARPA OFFICES
Defense SciencesInformation ProcessingMicrosystems Technology
Advanced TechnologySpecial ProjectsTactical Technology
Information ExploitationInformation Awareness
Internal Technology FlowInternal Technology Flow
1111
BioWarfare ThreatBioWarfare Threat
Update: The Trend Lines
• The growing threat of BW is generated by three disturbing trends:� The number of players possessing biological
weapons or seeking to acquire a biological warfare capability is increasing.
� Biological agents with increasing lethality are being developed.
� Detection of BW programs and the acquisition of BW-related capabilities is difficult.
• It happened here
National Intelligence Council Report: The Biological Warfare Threat, Jan 2001.
1212
Protecting Human AssetsProtecting Human Assets
Genome Sequencing
Sensors Protection Collective/
Building
Consequence Management
Advanced Diagnostics
Medical Countermeasures
Decontamination
Years Seconds to minutes
Minutes to hours
Minutes to hours
Hours to days
Hoursto days
Daysto years
1313
Simbiosys ProgramAnantha Krishnan, DSO
Novel Tools (Devices, Models, Databases, Algorithms ) for High Performance Biological/Chemical Sensing and
Processing
+
Simbiosys
Novel Processes, Experimental Methods, Computational Models and Design Tools that
significantly improve speed, sensitivity, specificity and efficiency of chemical/biological
processing and analysis
Novel Processes, Experimental Methods, Computational Models and Design Tools that
significantly improve speed, sensitivity, specificity and efficiency of chemical/biological
processing and analysis
Challenges� Experimental/Theoretical Characterization of the elements of a Bio-Molecular System :
�Molecular Recognition Elements (sensitivity, selectivity and speed)�Signal Transduction Elements (Signal Amplicationwith High SNR)�Bio-Fluidic Transport Elements (High Efficiency, Low Power Pumping, Valvingand Mixing Methods)
� Demonstration of device modelson design of Bio-Microsystems
Interface Between Biology and Micro/Nano-Technology
1414
p - AlGaNAlInGaN MQW
n - AlGaN
GaN buffer layer
Sapphire substrate
n - electrode
Grading Layer
n+ - GaNp+ - GaN
n - electrode
SUVOS - Semiconductor Ultraviolet Optical Sources John Carrano, Program Manager, MTO
Develop Solid-State UV Sources down to 280 nmCompared to conventional technology• Power consumption reduced by 50X• Size & weight reduced by 100X
LEDs andLaser Diodes:The Next Step
in efficientUV powergeneration
Enabling new classes of bio-agent detection systems
Emitter -Detector
sensor arrays
Bio-agentfluorescent signatures
Bio-Alertin every office
Visible LightUltraviolet
high energy Wavelength (nm) low energy200 300 400 500 600 700 800 900
Aerosol samplers �small and efficientfor MAV deployment
Low-co
st
mass p
roduc
ible
SUVO
S so
urce
s
100X
sm
aller
50X
mor
e ef
ficien
t
UV LED
Infrared
1515
M O S A I CMolecular Observation, Spectroscopy And Imaging using Cantilevers
Atomic Force Microscopyatomic scale, non-destructive,control
but only surface
Magnetic Resonance Imaging3D, non-destructive
but macroscale
Magnetic Resonance Force Microscopy3D, atomic scale, non-destructive, and with control
Technical hurdles� Signal processing� Nanofabrication� Readout
1616
BIOSBIOS
Techbase program to make plug & play (PnP) biocircuits that enable engineering of organisms for use as sentinel devices
1717
Bacteria enterthe cell in body (lung) or sensor
Bacteria invade alveolar cells
Bacteria internalize and multiply
Macrophage
Activity Based Detection: A Conceptual Framework
Alan Rudolph, DSO
Cellular or Tissue activity can be used as diagnostic or to engineer markers for sensors
Evaluate Activated Pathways
for Sensor
Report Infection
for Medical
Diagnostic
In vitro
In vivo
1818
Signs/Symptoms
100
Joint Pain
Cough
Chills
Vomiting
AppetiteLoss
Fever
Headache
Frequency (%)0 10 20 30 40 50 60 70 80 90
{{{{{{{{
Muscle Pain
TularemiaTreatment: Antibiotics -May be fatal if untreated.
Advanced Diagnostics�Why We Need It
Advanced Diagnostics�Why We Need It
No treatment currently available - Incapacitating (can cause severe disease at high doses).
SEB Toxicity
Treatment: Antibiotics -Incapacitating, not usually fatal.
Q-Fever
Early symptoms of many BW agents are flu-like and indistinguishable
1919
Signatures of ExposureSignatures of Exposure
Program Goal: Determine cell signatures of early exposure to BW pathogens and develop rapid signature diagnostics
Concept: Generate differential expression profiles and cDNA libraries from cells after exposure. Identify differentially expressed transcripts. Create gene reporter elements for diagnostic tests
WRAIR,Georgetown University, Stanford, Umea Sweden, APL
0
50
100
150
200
250
300
350
1 2 3 4
SEBAnthrax
0
100
200
300
400
500
600
700
800
900
1 2 3 4
SEBAnthrax
Changes in Expression of a GBP (unique to SEB vs. other toxins tested)
Changes in Expression of HIF-1 (common to many toxic agents)
SEB
Anthrax
SEB
Anthrax
2020
Unconventional Pathogen CountermeasuresJohn Carney, DSO
Unconventional Pathogen CountermeasuresJohn Carney, DSO
Technical Challenges:! Develop therapeutics effective
against all known and unknown (e.g. engineered) BW pathogens
! Develop effective multivalent vaccines with broad efficacy versus industry standard one bug one drug
! Enhance Immune system in order to eliminate the need for vaccines
Idea: Develop broad spectrum technologies that effectively counter potential BW threats to the US military and civilians
BroadBroad--Spectrum ApproachesSpectrum Approaches
Inhibition of Pathogen GrowthMIC (µM)
12.5MW6-15a
12.5SB28b
12.5SB20e
12.5DW522b
12.5DW523
6.25MW5304
6.25SB28d
106.25SB28c
6.25SB220b
6.25106.25DW520b
256.25DW522
1006.25MWTP
12.56.25MW6-15
12.53.125DW520
3.125103.12528C
Helicobacter pyloriBrucella abortusBacillus anthracisCompound
kills intracellular Brucella
not detrimental to cultured macrophages at >100µm
AntibacterialAntibacterial
Ibis Drug Discovery Strategy for RNA
Gene sequence data
RNA Subdomain Selection
Animal Studies
Screening
MASS Assay System HTS Functional assays
Lead Compound
DARPA Task 1
DARPA Task 2
DARPA Task 3,4
DARPA Task 5
USAMRIID Transition
AntiviralAntiviral
AntiAnti--Genomic Drug Binds to AGenomic Drug Binds to A--T rich T rich Targets and Blocks Essential Pathogen Targets and Blocks Essential Pathogen
GenesGenes
GeneSoft, Inc.
Essential Essential GeneGene
Essential Essential GeneGene
Essential Essential GeneGene
Essential Essential GeneGene
AnthraxAnthraxTularemiaTularemia
Small PoxSmall Pox
PneumoniaPneumonia
MalariaMalaria
Essential Essential GeneGene
AntigenomicsAntigenomics
Plants for Production of Vaccines and Antibodies
Edible plant vaccines stimulate immune responsesNature Medicine 4: 607-609 (1998)
Plant-expressed Abs provide protection in humansNature Medicine 4: 601-606 (1998)
Plants are an economical production system for subunit vaccine proteins to prevent infectious disease, and for antibodies to treat diseases or toxin exposure.
Bacterial or ViralStructural Gene
VaccinesVaccines
Breeding of Cross-Reactive Antigens
Natural evolution
Crea te reactivity aga ins t severa l antigenic variants
Exis ting Varia nts
Combine e pitopes
Ances tra l Molecule
VaccinesVaccines
CpG DNACpG DNA
MPMPDCDC
AdaptiveAdaptive protective immune protective immune responses: antigenresponses: antigen--specific antibodies (B cells), specific antibodies (B cells), killer T cells (killer T cells (slow, slow, enhance vaccinesenhance vaccines))
BBTT
NKNK InnateInnate protective immune protective immune responses: cytokines, responses: cytokines, chemokines chemokines ((immediate protectionimmediate protection))
Kill infected cellsKill infected cells
CpG DNA Activates Broad Spectrum Immune DefensesCpG DNA Activates Broad CpG DNA Activates Broad
Spectrum Immune DefensesSpectrum Immune Defenses
IFNIFN--γγ
CpG DNA is detected by immune cells CpG DNA is detected by immune cells (macrophage [MP], dendritic cell [DC], (macrophage [MP], dendritic cell [DC],
natural killer [NK])natural killer [NK])
Once alerted to �danger� by Once alerted to �danger� by injection of CpG DNA, the injection of CpG DNA, the activated immune system activated immune system protects the subject from protects the subject from infections for at least 2 weeksinfections for at least 2 weeks
ImmunotherapyImmunotherapy
PathogenesisPathogenesisRole of Host in Susceptibility to Viral Pathogens
(Why do I not catch foot and mouth disease from my cattle?)
Disease
binding
genome internalization
gene expression
protein processing
viral replication
pathogenic event
morphogenesis & release
Virus
Host
BroadBroad--Spectrum ApproachesSpectrum Approaches
Inhibition of Pathogen GrowthMIC (µM)
12.5MW6-15a
12.5SB28b
12.5SB20e
12.5DW522b
12.5DW523
6.25MW5304
6.25SB28d
106.25SB28c
6.25SB220b
6.25106.25DW520b
256.25DW522
1006.25MWTP
12.56.25MW6-15
12.53.125DW520
3.125103.12528C
Helicobacter pyloriBrucella abortusBacillus anthracisCompound
kills intracellular Brucella
not detrimental to cultured macrophages at >100µm
AntibacterialAntibacterialInhibition of Pathogen Growth
MIC (µM)
12.5MW6-15a
12.5SB28b
12.5SB20e
12.5DW522b
12.5DW523
6.25MW5304
6.25SB28d
106.25SB28c
6.25SB220b
6.25106.25DW520b
256.25DW522
1006.25MWTP
12.56.25MW6-15
12.53.125DW520
3.125103.12528C
Helicobacter pyloriBrucella abortusBacillus anthracisCompound
kills intracellular Brucella
not detrimental to cultured macrophages at >100µm
AntibacterialAntibacterial
Ibis Drug Discovery Strategy for RNA
Gene sequence data
RNA Subdomain Selection
Animal Studies
Screening
MASS Assay System HTS Functional assays
Lead Compound
DARPA Task 1
DARPA Task 2
DARPA Task 3,4
DARPA Task 5
USAMRIID Transition
AntiviralAntiviralIbis Drug Discovery Strategy for RNA
Gene sequence data
RNA Subdomain Selection
Animal Studies
Screening
MASS Assay System HTS Functional assays
Lead Compound
DARPA Task 1
DARPA Task 2
DARPA Task 3,4
DARPA Task 5
USAMRIID Transition
AntiviralAntiviral
AntiAnti--Genomic Drug Binds to AGenomic Drug Binds to A--T rich T rich Targets and Blocks Essential Pathogen Targets and Blocks Essential Pathogen
GenesGenes
GeneSoft, Inc.
Essential Essential GeneGene
Essential Essential GeneGene
Essential Essential GeneGene
Essential Essential GeneGene
AnthraxAnthraxTularemiaTularemia
Small PoxSmall Pox
PneumoniaPneumonia
MalariaMalaria
Essential Essential GeneGene
AntigenomicsAntigenomicsAntiAnti--Genomic Drug Binds to AGenomic Drug Binds to A--T rich T rich
Targets and Blocks Essential Pathogen Targets and Blocks Essential Pathogen GenesGenes
GeneSoft, Inc.
Essential Essential GeneGene
Essential Essential GeneGene
Essential Essential GeneGene
Essential Essential GeneGene
AnthraxAnthraxTularemiaTularemia
Small PoxSmall Pox
PneumoniaPneumonia
MalariaMalaria
Essential Essential GeneGene
AntigenomicsAntigenomics
Plants for Production of Vaccines and Antibodies
Edible plant vaccines stimulate immune responsesNature Medicine 4: 607-609 (1998)
Plant-expressed Abs provide protection in humansNature Medicine 4: 601-606 (1998)
Plants are an economical production system for subunit vaccine proteins to prevent infectious disease, and for antibodies to treat diseases or toxin exposure.
Bacterial or ViralStructural Gene
VaccinesVaccinesPlants for Production of Vaccines and Antibodies
Edible plant vaccines stimulate immune responsesNature Medicine 4: 607-609 (1998)
Plant-expressed Abs provide protection in humansNature Medicine 4: 601-606 (1998)
Plants are an economical production system for subunit vaccine proteins to prevent infectious disease, and for antibodies to treat diseases or toxin exposure.
Bacterial or ViralStructural Gene
VaccinesVaccines
Breeding of Cross-Reactive Antigens
Natural evolution
Crea te reactivity aga ins t severa l antigenic variants
Exis ting Varia nts
Combine e pitopes
Ances tra l Molecule
VaccinesVaccinesBreeding of Cross-Reactive Antigens
Natural evolution
Crea te reactivity aga ins t severa l antigenic variants
Exis ting Varia nts
Combine e pitopes
Ances tra l Molecule
VaccinesVaccines
CpG DNACpG DNA
MPMPDCDC
AdaptiveAdaptive protective immune protective immune responses: antigenresponses: antigen--specific antibodies (B cells), specific antibodies (B cells), killer T cells (killer T cells (slow, slow, enhance vaccinesenhance vaccines))
BBTT
NKNK InnateInnate protective immune protective immune responses: cytokines, responses: cytokines, chemokines chemokines ((immediate protectionimmediate protection))
Kill infected cellsKill infected cells
CpG DNA Activates Broad Spectrum Immune DefensesCpG DNA Activates Broad CpG DNA Activates Broad
Spectrum Immune DefensesSpectrum Immune Defenses
IFNIFN--γγ
CpG DNA is detected by immune cells CpG DNA is detected by immune cells (macrophage [MP], dendritic cell [DC], (macrophage [MP], dendritic cell [DC],
natural killer [NK])natural killer [NK])
Once alerted to �danger� by Once alerted to �danger� by injection of CpG DNA, the injection of CpG DNA, the activated immune system activated immune system protects the subject from protects the subject from infections for at least 2 weeksinfections for at least 2 weeks
ImmunotherapyImmunotherapy
CpG DNACpG DNA
MPMPDCDC
AdaptiveAdaptive protective immune protective immune responses: antigenresponses: antigen--specific antibodies (B cells), specific antibodies (B cells), killer T cells (killer T cells (slow, slow, enhance vaccinesenhance vaccines))
BBTT
NKNK InnateInnate protective immune protective immune responses: cytokines, responses: cytokines, chemokines chemokines ((immediate protectionimmediate protection))
Kill infected cellsKill infected cells
CpG DNA Activates Broad Spectrum Immune DefensesCpG DNA Activates Broad CpG DNA Activates Broad
Spectrum Immune DefensesSpectrum Immune Defenses
IFNIFN--γγ
CpG DNA is detected by immune cells CpG DNA is detected by immune cells (macrophage [MP], dendritic cell [DC], (macrophage [MP], dendritic cell [DC],
natural killer [NK])natural killer [NK])
Once alerted to �danger� by Once alerted to �danger� by injection of CpG DNA, the injection of CpG DNA, the activated immune system activated immune system protects the subject from protects the subject from infections for at least 2 weeksinfections for at least 2 weeks
ImmunotherapyImmunotherapy
PathogenesisPathogenesisRole of Host in Susceptibility to Viral Pathogens
(Why do I not catch foot and mouth disease from my cattle?)
Disease
binding
genome internalization
gene expression
protein processing
viral replication
pathogenic event
morphogenesis & release
Virus
Host
PathogenesisPathogenesisRole of Host in Susceptibility to Viral Pathogens
(Why do I not catch foot and mouth disease from my cattle?)
Disease
binding
genome internalization
gene expression
protein processing
viral replication
pathogenic event
morphogenesis & release
Virus
Host
Highlights:" 5th year of funding" USAMRIID technology transition partner
(10 transitions to date, 6 under discussion)" Possible development of 5 new
pharmacological therapeutics
2121
MicroVIC® Bio-aerosol Concentrators MicroVIC® Bio-aerosol Concentrators
• Technology:� Virtual Impaction (aerodynamic
sorting and concentrating)� Developer: MesoSystems
• Key Features:� Low power� Compact and versatile
� Wet or dry particle collection� Wet collection� Aerodynamic pre-filtering� Particle pre-concentrator for
triggers� Mass-producible (low cost)
• Commercialization in progress
Bioni� UV trigger byPacific Scientific Instruments
Continuous Air Samplerfor Lockheed Martin
0%
20%
40%
60%
80%
100%
0 2 4 6Particle Diameter (microns)
Sepa
ratio
n Ef
ficie
ncy
Experimental Computational
2222
BioBadge Wearable Bio-dosimetryBioBadge Wearable Bio-dosimetry
• Technology:� MesoSystems Rotating Impactor
combined with SRI International�s UPT Immunoassay
� Field exposure quantification for the individual
• Key Features:� Low power; field operation� Compact and light� 15-30 liters/min flow rate� 40% overall efficiency from Air
# Disk # Liquid sample• Commercialization status
� Laboratory testing in 2002� Field trials in 2003
0%
20%
40%
60%
80%
100%
Biological SamplerEfficiency
Extraction StationEfficiency
System Efficiency
none coating 1 coating 2 coating 3Coating:
2323
Personal Water Purification SystemsPersonal Water Purification Systems
Cryptosporidium parvum Inactivation with MIOX Disinfection Pen
-8-7-6-5-4-3-2-1012
0 10 20 30 40 50 60 70 80 90 100Time in minutes
Log
(Nt/N
o)
Beta Pen
Alpha Pen
Bleach
US EPA Purifier Standard
� New Generation Hydration System� Lightweight/reduced footprint for �on-the-move� operation (backpack)� Produces Gatorade-like nutrient drink from contaminated water via FO bag� MIOX pen/cap inactivates even extremely resistant microorganisms by 99.99%
� Tech Approach:� Effective mixed-oxidant chemistry from table salt� Smart electrochemical cell and circuit � Miniaturization of mechanical filters and purifiers� Pen/pump combo treats any water source� Low cost to produce� Working turbidity filtration issues
MIOX Disinfection Pen/Cap
Reverse Osmosis (RO)Pump / Advanced Membranes
2424
• FY03: Site selection
• FY04: System design and testing; on-site characterization
• FY05: Demonstration
Implement, optimize, and demonstrate a full-scale building protection system at a US military site
Immune Building Demonstration
Immune Building Demonstration
2525
Integrated Systems Experimentation Team
Integrated Systems Experimentation Team
Fort McClellan, Anniston, AL
• Battelle
• Auburn University
• Ensco, Inc.
• Fidelity Engineering Corp.
Contact: James E. Risser, [email protected]: James E. Risser, [email protected]
� Gage-Babcock& Associates
2626
Bio Sensors ContextBio Sensors Context
Antibodies
hours minutes seconds
Surveillance
Det
ectio
n ab
ility agent specific
reducedfalse alarms
bio particles
any particles
threat particles
MassSpec
weeksCapabilitytoday
CulturePCR
APS
?
Goal
Forensics Early warning
2727
Biosensor Technologies
Upconverting Phosphor Technology(UPT)-SRI International (Menlo Park, CA)Handheld Biosensor
-University of Washington -Argonne National Laboratory (ANL)-JHU/APL - Food and Drug Administration (FDA)
(DARE) DARPA Antibody ReplacementEnhancement Team
-University of Alabama-Archemix-University of Texas at Austin-Polytechnic University-University of Missouri-Auburn University
Ion-channel Biosensor Team-Auburn University -Sandia National Laboratory-Rush-Presbyterian -Polytechnic University
Micro Array of Gel-Immobilized CompoundsMAGIChipTM
IdentifyingTechnology
Critical Sensor Technology
ANTIBODY