Dr. Steven G. Wax, Director Dr. Brett P. Giroir, Deputy Director Dr

Dr. Steven G. Wax, Director Dr. Brett P. Giroir, Deputy Director Dr. Carey Schwartz, Program Manager Applied and Computational Mathematics Program DARPA’s Mission

DARPA’s mission is to prevent technological surprise from harming our national security by sponsoring revolutionary, high-payoff research that bridges the gap between fundamental discoveries and their military use DARPA Accomplishments

19601960

UCAV Global Hawk Saturn Vela Hotel

19701970 Ground TMR MEMS Surveillance Radar ATACMS 20002000

JSF MALD M-16 Rifle JSTARS 19801980 Uncooled IR Stealth Fighter Arpanet 19901990 BAT

Sea Shadow GPS Taurus Launch Predator Vehicle DARPA Organization

Director, Tony Tether Deputy Director, Bob Leheny

Information Exploitation Tactical Technology Special Projects Advanced Technology Ted Bially Art Morrish Amy Alving Dave Honey Robert Popp/Robert Tenney Gary Graham/Stephen Welby Joe Guerci Larry Stotts Air/Space/Land Platforms Chem/Bio Def Systems Sensors Unmanned Systems Counter Underground Assured C3ISR Facilities Space Operations Exploitation Systems Space Maritime Laser Systems Sensors/Structures Command & Control Early Entry/Special Future Combat Systems Navigation/Sensors/ Forces Planning / Logistics Signal Processing

Information Processing Joint Unmanned Defense Sciences MicrosystemsTechnology Steven Wax Technology Combat Air Systems Ron Brachman Zach Lemnios Mike Francis Brett Giroir Barbara Yoon John Zolper Bio Warfare Cognitive Systems Electronics Common Systems & Defense Computational - Optoelectronics Technologies Technologies Perception MEMS X-45 System Biology Representation & X-47 System Materials & Reasoning Combined Devices Microsystems Mathematics Learning Natural Communication

APPROVED FOR PUBLIC RELEASE 39873 DARPADARPA Strategic VisionVision

• Strategic Thrusts • Precision detection, tracking, and destruction of elusive surface targets • Characterization of underground structures • Force multipliers for urban combat • Networked manned & unmanned attack operations • Assured use of space Maintain the technological • Cognitive systems Maintain the technological superioritysuperiority of of the the U.S. U.S. • Bio-Revolution militarymilitary and and prevent prevent • Robust, secure self-forming networks technologicaltechnological surprise surprise … … • Enduring Foundations High-payoffHigh-payoff research research that that • Materials bridgesbridges the the gap gap between between • Microsystems fundamentalfundamental discoveries discoveries andand their their military military use. use. • Information Technologies Defense Sciences Office

Exploit discoveries and innovations Paradigm shifts in defense in science and engineering capabilities

Mine the “Far Side of the Breakthroughs to Exploit Far Side” Biological Sciences Materials & Devices Mathematics Diverse Disciplines Diverse Programs Engineering, Physics, Materials, Nanoscale Mathematics Structures

Medicine, Microbiology, Hardware/Devices Biochemistry in the hands of soldiers DSO vs. others

• “The flying machine • “We started assembly which will really fly might today” be evolved by the combined and – Orville Wright’s Diary continuous efforts of • 9 October 1903 mathematicians and mechanicians in from one million to ten million years” –The New York Times • 9 October 1903 DSO – Technical Personnel

Dr.Dr. Steven Steven G. G. Wax, Wax, Dir Dir Dr.Dr. Brett Brett P. P. Giroir, Giroir, Dep Dep Dir Dir

Dr.Dr. Joseph Joseph Bielitzki Bielitzki Dr.Dr. Valerie Valerie Browning Browning Dr.Dr. Geoff Geoff Ling Ling (LTC (LTC (p), (p), USA) USA) Dr.Dr. Leonard Leonard Buckley Buckley Dr.Dr. John John Lowell Lowell (Maj, (Maj, USAF) USAF) Dr.Dr. Ralph Ralph Chatham Chatham Dr.Dr. John John Main Main Dr.Dr. Leo Leo Christodoulou Christodoulou Dr.Dr. Ben Ben Mann Mann Dr.Dr. William William Coblenz Coblenz Dr.Dr. Rick Rick Satava Satava Dr.Dr. Douglas Douglas Cochran Cochran Dr.Dr. Carey Carey Schwartz Schwartz Dr.Dr. Mildred Mildred Donlon Donlon Dr.Dr. Morley Morley Stone Stone Dr.Dr. Eric Eric Eisenstadt Eisenstadt Dr.Dr. Terrence Terrence Weisshaar Weisshaar Dr.Dr. Anantha Anantha Krishnan Krishnan Dr.Dr. Stuart Stuart Wolf Wolf DSO Office Thrusts

Materials Mathematics Biological & Devices Sciences

Structural Materials and Applied Mathematics Biological Warfare Defense Components

Smart Materials and Basic Research in Maintain Human Performance Structures Mathematics

Functional Materials Enhanced System Performance

Power and Water Bio-Materials TheThe ParadoxParadox ofof MathematicsMathematics

• Users of mathematics think that all the mathematics necessary for progress already exists and that practitioners already have sufficient mathematical skills with these tools to proceed. – Therefore, we don’t need mathematicians and can concentrate on scientific and technological problems at hand. • Mathematicians feel that applications are secondary and practitioners really don’t understand why mathematics is important or how to use it. – Therefore we don’t need practitioners and can concentrate on inventing new mathematics. • Thus both groups feel, since the other is clearly self- serving and misguided, that they can safely ignore each other.

MathematicsMathematics at at DARPA: DARPA: Focused Focused effort effort that that both both incorporates incorporates existingexisting mathematics mathematics and and develops develops ne neww mathematics mathematics to to be be used used at at criticalcritical points points in in the the solutions solutions of of many many DARPA-hard DARPA-hard DoD DoD problems. problems. Exploiting Mathematics

DecreasingDecreasing TimeframeTimeframe OfOf OperationsOperations OnOn TheThe BattlefieldBattlefield IsIs AtAt OddsOdds WithWith TheThe TrendTrend TowardsTowards AnAn IncreasinglyIncreasingly ComplexComplex BattlefieldBattlefield Environment.Environment. OverOver 50%50% OfOf GainsGains InIn SpeedSpeed HaveHave BeenBeen DueDue ToTo MathematicsMathematics (Improved(Improved Algorithms)Algorithms) NotNot Moore’sMoore’s LawLaw (Computer(Computer Speed).Speed).

• Determining Representations -- Optimizing Dimensionality!

• Representation and Analysis of Large and/or Disparate Data Sets • Adaptive Sensors and Waveforms • Modeling of Materials, Physics and Biology • Quantifying and Bounding Uncertainty and Robustness The 21st Century Battlespace Advanced Computational Math

Virtual Electromagnetic Testrange Integrated Sensing & Refine new mathematical Processing

developments and bring them to Physical Field practice in design of LO air (continuum) vehicles Numerical analysis (fast multipole PHYSICAL method) LAYER Computational geometry Establish a consortium of major PROCESSING LAYER airframers Symbolic Output

EXPLOITATION ISP closes the

sensing system loop system sensing LAYER

• Globally optimized sensor system designs allow the integration of independently optimized sensor components PerformancePerformance GraphsGraphs

Exploiting Complex Systems

Method of Moments (MOM) Fast Multipole Method (FMM)

# flops # flops 14 ++ 18 10 • 10 4

Full Vehicles Full Vehicles 12 13 10 • 10

O(N^2) 3 O(N log N) Components Components 12 12 10 10 Details Details 10K 25K 1,000K+ 10K 25K 1,000K+ N = # unknowns N = # unknowns PredictingPredicting MaterialMaterial PropertiesProperties

Property of interest and Goal Materials of Interest • Nonlinear optical materials

Theoretical description • Diluted magnetic semiconductors •Macroscopic • Mesoscopic • Thermoelectrics •Microscopic • Ferroelectrics my, mx depend on the electronic structure • High energy density materials Ab initio electronic structure calculations Ab initio electronic structure calculations for many structures and compositions for many structures and compositions Direct Inverse Method MultiscaleMultiscale methods methods

SearchSearch Algorithms Algorithms

errors errors Optimized material Optimized material errors

Experimental Experimental validation validation TimeTime ReversalReversal

Propagation Exploit multiple scattering for Single Scattering Event Path medium image formation and a communication e a Two Scattering All paths other than the direct path Event Path AB from A to B through the propagation Direct Path medium is multipath Multiple scattering can increase the effective aperture from a to ae. Multiple Scattering Event Path

Testbeds

Image Formation and Antennas Target Signature Propagation HumanHuman AssistedAssisted NeuralNeural DevicesDevices

UseUse brainbrain activityactivity toto directlydirectly controlcontrol prostheticsprosthetics andand peripheralperipheral devicesdevices • Progress – Open loop, brain control of “prosthetic” arm – Beginning demonstration in human subjects – Coordinating with VA – Begin correlating to non-invasive electric (EEG) or magnetic (MEG) fields Geo*Geo* ---- AddressinAddressingg GeometricGeometric ShortfallsShortfalls

• New Representations for Surface and Geodetic Data – 100X improvement in storage with no loss of precision in end application – Easily Conflated/Deflated (30-60 Hz) for images, 1 Hz for gravity • Automated Registration – Tactical Imagery (256 x 256) to Digital Point Precision Data Base at 30 HZ (500 x improvement – Contrast, Illumination, and Scale, Invariant Methods Representations • Error Management – Multiresolution representation that supports multiple applications with a variety of accuracy requirements Topological Data Analysis

RECOGNIZE THE PLAYING FIELD BEFORE THE GAME STARTS

• Discovery of the shape of a data set is the necessary first step toward finding high value targets.

• It is striking that this fundamental question has been ignored in classical statistical and data analysis.

••DevelopDevelop thethe mathematicalmathematical conceptsconcepts andand techniquestechniques toto determinedetermine thethe “statistical“statistical playingplaying field”field” for for massivemassive datadata setssets •• DevelopDevelop furtherfurther toolstools toto exploitexploit thatthat knowledge.knowledge. SStoctochhastastiicc && PPerturerturbbatatiionon MethodsMethods inin PDEPDE SystemsSystems

• Stochastic treatment of fundamental PDEs modeling physical systems – E.g., Maxwell, Navier-Stokes, Helmholtz,

Poisson, Laplace Rough surfaces • Interpolation/extrapolation methodology (with error characterization) for multi- parameter problem spaces • Hybridization across scale

Design of configurable systems Matching boundary conditions may allow “teleporting” solutions Materials

Low Cost Titanium Structural Amorphous Metals • Bulk metallic glasses and their composites for revolutionary DoD capabilities

• Four Competitive Routes Being Examined • Electrolytic (TIMET, MER) • Fluidized Bed (SRI) • Na Reduction • Target: < $4/lb – Promise for $2.00

30µm

Ti-6-4 Alloy

Baseline Ti alloy

1mm First atomic structural model for metallic glasses Low Cost Titanium

Al2O3 Al

TiO2 Ti

What’s New

TiO2 O2

• Several competitive routes being APMTIAC Quarterly V6 No2 examined:

Electrolytic

Fluidized Bed

Na Reduction Exhaust

Ti (Al, V) • Target: Ingot at < $4/lb (vs. $16+/lb) deposition

TiCl2,TiCl3

H2 + AlCl3, VCl4 Cost estimates as low as $1.00-$2.50/lb Ti Sponge Cost estimates as low as $1.00-$2.50/lb Ti (Al, V) pellets

TiCl4 Friction Stir Processing

• Directed, localized, controlled σ microstructural modification ω • Improve local structural, corrosion properties • Induce local superplasticity. v

Property As cast Ni-Al FSP Bronze Microstructure • Casting/Repair Ni-Al Bronze Propeller for VA Class Sub Yield strength 214 MPa 591 MPa • Demonstrated at NSWC, Carterock • Planning transition to Philadelphia Tensile strength 445 MPa 824 MPa Navy Yard Elongation (%) 20 24 Complete forming in corners Incomplete forming in corners and edge following FSP and edge without FSP Superplastic Forming - Edges Only! New Ways to Think about Structures

Synthetic Multifunctional Materials Morphing Aircraft Structures • Combine structure with such functions as Loiter – Power Attack – Sensing and Communication – Self-Healing – Unique Electromagnetic Properties 1.5 – 2.0 x increase range

177%177% wing wing area area increase increase 30o 30oeffectiveeffective wing wing sweep sweep change change 71%71% span span increase increase

Composite Flex Skin

Composite Flex Skin with Wire Reinforcement

6 Compact Actuators

Flex Torque Tube Spars & Ribs Lattice Skin Support Morphing Aircraft Structures

••StaticStatic design design generates generates single single mission mission ••MorphingMorphing enables enables multiple multiple missions missions ––ActiveActive wing/skin wing/skin structures structures to to provide provide radical radical improvementsimprovements in in aircraft aircraft and and missile missile performance performance Long Endurance ISR

Circle represents the best that a single Takeoff: Low Altitude wing can do Sustained Turn: Climb: High Altitude Low Altitude

Instant Turn: Climb: Low Altitude Mid Altitude Attack Configuration

Loiter: High Cruise: Composite Flex Skin Altitude Low Altitude

Dash: Cruise: Mid Altitude Mid Altitude Bat Wing 10

Bat Wing 20 Acceleration: Cruise: Mid Altitude High Altitude Bat Wing 30 Bat Wing 42

Composite Flex Skin with Wire Reinforcement • 2.1x increase range at cruise • 1.5x increase range at loiter 6 Compact Actuators

• 1.3x increase range at dash Flex Torque Tube Spars & Ribs Lattice Skin Support Power and Water

Water Purification Fuel Cells and Generators Water Purification and Harvesting

Hydrophilic Hydrophobic MIOX Disinfection Pen

EPA Purifier Protocol Results for Disinfection Pen

EPA Requirement Pen in GTW 1 Pen in GTW 2 9

5 4

3 LOG Inactivation LOG 2

0 Bacteria Viruses Cysts Organism Type

6”long, 4 ounces • Uses common salt (salt tablets or MRE salt) and camera batteries - 250 liters per battery set • Fault indicators for low salt and batteries • Has passed US EPA “Purifier Protocol” • Works Against Cryptosporidium (chlorine does not!) • Military Testing/Demonstrations: • Testing in Afghanistan, Iraq • Special Forces PalmPalm PowerPower ProgramProgram

55 BA-5590 +2 BA-5800 = 125 lbs … A typical requirement for ONE operational day for a radio reconnaissance team!!!

Portable power sources with up to 10 Portable power sources with up to 10 4.4” -- 15x 15x the the energy energy density density of of today’s today’s batteries using JP8 2.4” batteries using JP8 9”

Interim Success: Methanol Fuel Cell 800 Whr/Kg = 6x Batteries Materials for Logistics Water Harvesting

30-60 Wh/L

10-20 Wh/L EnergyEnergy EfficientEfficient TechnologiesTechnologies toto RemoveRemove 02040 60 10080 WaterWater fromfrom AirAir % Relative Humidity 50 %RH 30 %RH

Oasis (no water;750 W) 560 Whr/L

Water delivery by truck Æ 1 Wh/l/mile Water delivery by helicopter Æ 15 Wh/l/mile

Hydrophilic Hydrophobic dry, processed input air air low water higher water activity activity

desiccant solution w/ Moist 0.5-1 mm Dry air high water activity air polypropylene mesh ? = 1300-3000 psi

Air/LiX Liq Desiccant 100 micron ss mesh - electrode (A) Single-stage, high Mass Exchanger 5-10 micron silica particles pressure RO unit, or 0.7 micron Nanoglass binder (B) Series of lower 0.1 micron Al + electrode 25 micron Kapton pressure modules desiccant solution w/ low water activity Materials for Logistics SuperconductingSuperconducting HybridHybrid ElectronicsElectronics

Low Loss High Temperature (65K)

Superconductors and Advanced 19 MW Motor Controller and Power Distribution Electronics Ceramic Capacitors Philadelphia Navy YardATG ATG SWGR IR Suppr

MTG Exhaust Zone 2 Dist

Zone 1 Dist Superconducting 4 Hybrid Power

) MTG Inlet Control

3 Conditioning * Room MTG AIM SWGR 23 MVA Transf (if req’d)

3 Waterbrake MTG SWGR AIM Converters 21 MVA Transf (2) AI Motor PM Motor Drive LO Module : 30 MW Navy Electric AIM HF PM Motor CaseCase study study: 30 MW Navy Electric Propulsion Motor Drive and Power Propulsion Motor Drive and Power Electronics (SAIC) Electronics (SAIC) 2 reduction in volume (from ••14x14x reduction in volume (from Motor 176.8 m3 to 15 m3 ) 176.8 m3 to 15 m3 ) reduction in mass (from ••10x10x reduction in mass (from 121,237 kg to 12,000 kg ) 121,237 kg to 12,000 kg ) 1 • 3x decrease in loss (from 7.1% to

Power Density (MW/m Density Power • 3x decrease in loss (from 7.1% to 2.8%) 2.8%)

O.4 Navy Baseline Conversion Ramp to * Decomposition to YBCO Oxygenation xygenation YBCO Formation Current AC YBCO Cryo Capacitor MobileMobile InteIntegratedgrated SustainableSustainable EnergyEnergy RecoveryRecovery (MISER)(MISER) • Objective: Innovative approaches to convert military packaging waste generated in the field to useable fuel sufficient to power on-site operations • Impact: – Reduce military waste footprint = – Increase energy produced on- site

7 pounds of 1 gallon JP-8 or JP-8 plastic waste = Molten metal anode Cathode Depleted Pre- Air processing chamber CHx

H2 CO C CO H2 C

(T=600+C) Solid oxide H O, CO Air 2 2 electrolyte ExternalExternal CombustionCombustion SoldierSoldier PortablePortable GenGen--SetsSets

• Stirling Engine Generator – 400 Watts continuous power (10% Electrical efficiency) – Dry Weight 37 pounds – Volume 1 ft3

• Steam Engine – 1,000 Watts – 8-hour mission, with fuel tank and JP-8 fuel (8 hrs min. operation before refill) – 1000 hrs MTBF, 200 hrs MTBPM; 95% reliability – >17% fuel-to-electric efficiency – 65 W/kg specific power – < 2 cu. ft volume SmallSmall--UAVUAV EngineEngine (SUAVE)(SUAVE)

Change Paradigm of Small Turbine Engines New Materials and New Designs

Critical Challenges • Ceramic Hot Section Components • Combustor • Fuel Injector • Recuperator • Bearings • Motor-Generator • Mechanical and Thermal Design FunctionalFunctional Materials

MetaMaterials SpIns IN SemIconductors

Revolutionary new class High DesignDesign andand buildbuild newnew materialsmaterials withwith Revolutionary new class High speed, low power semiconductor propertiesproperties (microwave,(microwave, magnetic,magnetic, etc.)etc.) speed, low power semiconductor electronics based on the spin notnot availableavailable inin naturenature electronics based on the spin degreedegree ofof freedomfreedom ofof thethe electronelectron

Exchange-coupled Hard phase Soft phase nanocomposite magnets (aligned) Conventional Spin Electronics Electronics Moving Charges Coherent Spins -

Positive index lens Negative index lens Spin-FET

R V f = g n −1 2DEG

A lens with n=+3 has the same focal length as n = -1! MetaMeta--MaterialsMaterials

Exchange-coupled Hard phase Soft phase nanocomposite magnets (aligned) DesignDesign andand buildbuild newnew materialsmaterials withwith propertiesproperties (microwave,(microwave, magnetic,magnetic, etc.)etc.) notnot availableavailable inin naturenature

ferromagnets µ Desired microwave design space No propagation

Meta-materials?

ionosphere superconductors ferrites Nanocomposite record dielectrics >40 MGOe Vs ε 20 MGOe

No propagation LeftLeft-handed-handed media: media: aa whole whole new new class class of of metamaterials metamaterials!!!!!! •• “negative“negative Doppler Doppler shift, shift, •• “backwards”“backwards” Cherenkov Cherenkovradiation radiation •• novelnovel optical optical properties properties

NIM Lenses Exploiting New Physics

Negative Index Materials Slowing Light • Extend the phenomenon of “left- • Push current and future scientific handed” or negative index materials research towards DoD applications to optical wavelengths, while by exploring the limits of potential improving the bandwidth and technology that result from minimizing losses in negative slowing, storing, and manipulating refraction materials light in various media Negative Refraction Reverses Optical Geometries Positive index lens Negative index lens R f = n−1

A lens with n=+3 has the same focal length as n = -1!

D D/4

Patch antenna array

Negative index lens Conventional Scanning Multiple or Dielectric lens scanned high gain beams SlowSlow LightLight

ExploringExploring thethe limitslimits ofof potentialpotential technologytechnology thatthat resultresult fromfrom slowing,slowing, storing,storing, andand manipulatingmanipulating lightlight inin variousvarious mediamedia SS pp II nn ss II NN SS ee mm II cc oo nn dd uu cc tt oo rr ss

BasicBasic Research Research to to Explore Explore Potential Potential Paradi Paradigmgm Shift Shift in in Classical Classical and and Quantum Quantum Electronics Electronics Conventional Spin Electronics Quantum Spin Electronics Electronics Moving Charges Coherent Spins Coupled Single Spins -

Information in number of charges Information in phase Information in Entanglement Transparent link from Totally new paradigm for Computation to Communications Computation and Communication Low Power, Increased Speed Ultralow Power, Exponential Speedup

New Spin Devices New Spin Science • Spin devices operating at RT • New Ferromagnetic Semiconducting • Novel spin heterostructures Materials • New devices operating above 100 GHz • Demonstrated Spin Transport and Control • Enabler for spin qubits • Discovered Totally New Spin Effects • Novel photonic and spin coherent devices • Novel new sensors, oscillators Femtosecond High Optical Energy Integrated Compact Semiconductor Laser

Micromachining Objective: LIDAR Directed Energy • Demonstrate in shoebox size a highly efficient (~50%), compact, short pulse (<10-12 sec),high peak power (>1012 W/sq-cm) integrated laser diode IPI GCSEL Device structure based on semiconductor lasers and amplifiers Optical communications Spectroscopy Impact: 40 )) • Ultra-short pulses 22 pure thermal ca ablation damage ili 20 s decrease the energy ed e us id f or 10 flu density ablation threshold m ui lc ca > 100x over conventional 5 lasers 3

• Ultra-short pulses can 2 1/2 Fdamage ~ τp remove any material (J/cm (J/cm threshold threshold Damage Damage 1 0.1 1 10 100 1000 Pulsewidth (ps) Precision Inertial Navigation Systems

• Develop atom interferometers for inertial navigation systems – Use wave nature of atom to build atomic analog to Mach-Zender interferometer • Laser cool atoms (using Magneto-Optic Trap technology) to form two slow (5 m/s) High Flux Cold counter-propagating atomic Atom Beam beams

• Stimulated Raman laser pulses Accelerometer for Gravity act as beamsplitters and mirrors Gradiometer – Similar pulse sequence to atomic clocks, NMR gives high precision Accelerometer / from phase-sensitive measurement Gyroscope Cell • Technology pushes: – Accelerometers with bias ~1ng – Gyroscopes with bias ~1 µdeg/hr – Moving platform capable gravity gradiometry – Develop photonics integrated with atomic systems Nano-Magnetics in Biology

Existing technology!!

Dynabead™ Nanoparticle 1 : 1 scale

NdFeB Sphere

500 nm

This is where we need to be in order to interface with cells and biomolecules! Engineered Bio-Molecular Nano-Devices and Systems (MOLDICE)

Ion Flow Through Channel

ssDNA Antigen Antibody

Gel

Electronic CircuitrySilicon Circuitry

Electrical Signal Waveform Molecular Scale Array Platform Control/Precision Single Device Architecture ¾¾ScalableScalable Device/InterfaceDevice/Interface ArchitecturesArchitectures forfor DirectDirect andand DynamicDynamic ExtractionExtraction ofof StochasticStochastic SignalsSignals ¾¾ArrayArray IntegrationIntegration andand ArrayArray ProcessingProcessing TechniquesTechniquesforfor UniqueUnique Bio-Bio- SignatureSignature IdentificationIdentification forfor DifferentDifferent TargetTarget MoleculesMolecules EnEnggineeredineered BioBio--MolecularMolecular NanoNano-- DevicesDevices andand SystemsSystems

Ion Flow Through Program Accomplishments Channel • Demonstration of First Scalable Platform for Embedding Protein Ion Channel Sensors –

• Demonstration of First Stable Interface (~ 1 week) for the Platform (as Compared to Few Minutes Stability with Current Technology)

Gel • First Extraction of Stochastic Signals from Source Drain the Platform (Reveals Identity as well as Silicon Concentration of Targets) Electrical Signal Waveform Reproducible Pores of < 5 nm Demonstrated for Ion Channel Insertion ; Signal Extraction for Simulant Agents Underway

*A simulant for an organoarsenic chemical warfare agent BiologyBiology atat DARPADARPA

Protecting Human Assisted Human Assets “Defending against Simulation of Neural Devices Biological threats” Bio- Molecular Microsystems Biological Adaptation Enhancing Maintaining Nanostructure System Performance Human Combat “Using Biology to Performance in Biology BioInterfaces Enhance “Deploy at Peak, Defense Systems” Maintain at Peak”

Tools BioComputation ProtectingProtecting HumanHuman AssetsAssets

Genome Sensors Protection Consequence Advanced Decontamination Sequencing Collective/ Management Diagnostics Building Medical Countermeasures

Years Seconds to Minutes Minutes Hours Hours Days minutes to hours to hours to days to days to years DSO BW Defense Programs

• Pathogen Countermeasures Develop broad spectrum therapeutic for any BW agent including the unknowable Anti-Genomic Drug Binds to A-T rich Targets and Blocks Essential Pathogen (genetic engineered) that effectively counter potential BW threats to the US military Genes

and civilians dsRNA target

Essential Gene

- Accelerated Anthrax Therapeutics Essential Ebola Gene Essential Plague Gene Essential Small Pox Taking anthrax off the table Gene Tularemia - Rapid Vaccine Assessment Anthrax GeneSoft, Inc. Biological Warfare Defense • December 2000 35 To provide the warfighter with better vaccines in less time with lower development costs • BioSensor Technologies Development of new highly specific biosensor systems that reduce false alarm rates and increase the ability to detect and identify multiple BW agents - Tissue-Based Biosensors Develop a wide variety of applications critical to defense needs based on using the response from living cells and tissues as the detector component of a working sensor or

brucella2 brucella6 brucella24 Anthrax2 Anthrax4 Anthrax8 Bot2 bot6 bot24 CT1 CT4 diagnostic system CT8 CT16 CT48 CT72 DEN4 DEN8 DEN24 Plague1 Plague2 Plague4 Plague8 SEB3 SEB6 SEB12 SEB18 VEE1 V EE4 VEE8

• Advanced Diagnostics 5

Develop new technologies for addressing early pre-symptomatic 3

(TNF)-related PI3-kinase P85-alpha transcription factor aurora-related kinase myelin proteolipid erythrocyte urea CD70 antigen 1 activation protein ATF2 1 (ARK1) protein (PLP) transporter signatures and systems for early warning and detection of exposure (TRAP)

to BW agents. -1 • External Protection Novel technologies to decontaminate air and water DSO BW Defense Programs

Pathogen Countermeasures Rapid Vaccine Assessment

BioSensors Advanced Diagnostics

Volatile compounds are significantly different with SEB administration before symptoms appear

Uninfected pig SEB infected pig after 1 Hr External Protection Realtive AbundanceRealtive

T B M B 3 B H 2 o e - t u , u e P o e 4 6 l n t u t t l y x - - y h h u ( B e z l a 1 r o y e e a d i n o n - s x l n t e o e l o e - a y a e c x ( d 1 c - l x a o p c y , t h n p 1 o h o - y e r n e h 1 o d d Staphylococcus o - i e n p p m l r y r o y l o l e enterotoxin B (SEB) - x ) o p y t p h x a y i n h m e l a e e l n t o h l y l ) - Pathogen Countermeasures

The PC program addresses unmet needs in combating infectious disease.

PATHOGENPATHOGEN COUNTERMEASURESCOUNTERMEASURES

Pathogen-directed Host-directed Antigen- Pathogen-directed Host-directed Antigen- ExperimentalExperimental countermeasures countermeasures specific countermeasures countermeasures specific systemssystems andand immunityimmunity •• Attack Attack thethe pathogenpathogen •• Recruit Recruit body’sbody’s defensedefense ValidationValidation withwith biochemistrybiochemistry andand system.system. •• Move Move vaccinesvaccines molecularmolecular biology.biology. thth • Test products in •• Enhance Enhance endogenousendogenous outout ofof thethe 1818 • Test products in vivo. •• Create Create newnew methodsmethods forfor capabilitycapability toto resistresist century.century. vivo. toxintoxin inactivation.inactivation. infection.infection. •• Identify Identify newnew •Find•Find newnew grounds to •• Develop Develop newnew antigenicantigenic grounds to explore. strategiesstrategies forfor targets.targets. explore. immunomodulation.immunomodulation.

PC will provide therapeutics for emerging diseases, solutions for antibiotic resistance, and broad-based immunity. Pathogen Countermeasures

Using Phage Lytic Enzymes to Specifically Control Pathogenic Bacteria Vincent Fischetti, Rockefeller University

Targets: S. pyogenes; S pneumoniae; S. aureus; E. faecalis.

Bacillus RSVF treated with PlyG lysin—actual time 2 min Progress/Demonstrations: Phage lytic enzymes from S. pyogenes, and S. pneumoniae phage have been cloned and produced recombinantly; Significant survival of enzyme-treated animals has been shown. PathogenPathogen CountermeasuresCountermeasures

Major Transitions

Project Goals PI/Organization Transitioned to

Antibacterial activity of heterobiaryl guanidines Griffey/IBIS USAMRIID

Gene shuffling to restructure enzymes, proteins and other biological Whalen/Maxygen USAMRIID, agents to make them more potent; DNA-Tetravalent Dengue fever Navy vaccine development Human acetylcholinesterase production from transgenic plants Arntzen/ASU USAMRIID Genetic countermeasures: Regulation of pathogen gene expression small Tanaka/GeneSoft USAMRIID molecule anti-genomic therapeutics (SMATs)

Identification and development of a new, broad spectrum antibiotic for Lee/Anacor Pharm USAMRIID pathogens targeting CcrM DNA methyltransferases Superantigen toxin antagonist and vaccines Kaempfer/HUJ USAMRIID Nonspecific immune stimulation by synthetic lipid A analogues Persing/Corixa USAMRIID Molecular database construction and mining: A general approach to Pang/Mayo USAMRIID unconventional pathogen countermeasures Nanomolecule-Based agents for pathogen Baker/U Mich Commercial countermeasures/decontamination TakingTaking AnthraxAnthrax offoff thethe TableTable

Performer Stages of Effort Progress Therapy Coley Pharma Early Activation of innate immunity by CpG for AVA/CpG (CpG as Mid enhancement of existing anthrax adjuvant set for Phase I vaccine (AVA) and increased natural clinical study soon). immunity/protection against pathogens, IND Summer of 04 including anthrax Use as monotherapy in testing

GeneSoft Early Regulation of pathogen gene Lead Compound Mid expression by using DNA-binding Testing polyamides to attack the AT rich DNA of pathogens Anacor Early Targets an enzyme that methylates Lead Compound Mid DNA and is essential for bacteria Testing in Rodent survival but does not exist in human Model cells and is thus harmless to the host Spring 04 (IND to follow if successful) Enzybiotics Mid Using bacteriophage enzyme specific to IND Spring of 04 Late anthrax to lyse (disintegrate) anthrax bacteria

Pharmathene Mid Use of Inhibitor of “protective antigen” IND Filed Late that blocks the effect of anthrax toxin on a cell RapidRapid VaccineVaccine AssessmentAssessment

High throughput vaccine Capable of in vivo cellular & development and testing humoral responses The Real Immune System Fast and no requirement for lymph thymus node animals

spleen

Peyer’s patch

bone marrow

2 cm Immune System in a Bottle

Ultimate Goal: to build an interactive in vitro immune system. 53 RapidRapid VaccineVaccine AssessmentAssessment

Demonstration of Human Response from “In Vitro” Tissue

B cell T cell

100

70 Response In Vivo % MHC II positive Cytokine production Ab avidity Ab production Ab affinity

• B lymphocytes actively produce IgM and IgG • Antibody avidity and affinity are nearly identical • T lymphocytes actively produce cytokines (i.e. Il-2) • Immune cells carry human MHC class II antigen

3D CONFORMAL PRINTER PrePre--symptomaticsymptomatic DiagnosisDiagnosis

Creating pathogen-specific reagents, developing prototype components and systems, and investing in high risk diagnostic innovations

Diagnostic Objectives:

• Identify exposure before symptoms appear • Develop probes and reagents • Eliminate sample handling acquisition, and preparation • Develop advanced hardware for detection/readout BreathBreath asas aa DiagnosticDiagnostic

To identify exposure before symptoms appear in the warfighter using rapid non-invasive methods

• Current methods focus on agent specific or symptomatic detection. • Potential exposure to unknown agents is highly probable, and rapid non- invasive technologies DO NOT CURRENTLY EXIST.

Volatile compounds are significantly different with SEB administration before symptoms appear

Uninfected pig SEB infected pig after 1 Hr UNKNOWN AGENTS Breath

Current Technology AbundanceRealtive Agent Known Pre- Specific T B M B 3 B H 2 o e - t u , Presentation u e P o e 4 6 l n t u t t l y x - - Symptomatic y h h u ( B e z l a 1 r y e e n o a d - i Agents o n n o s l t e x e - Detection l a o e e x a y ( d c with Symptoms c - l x a o 1 p c y , t h n p 1 o h o - y e r n e h 1 d d o Staphylococcus o - i e n p p m l r y r o y l o l e enterotoxin B (SEB) - x ) o p y t p h x a y i n h m l a e e e l n t o h Time l y l ) - NasticNastic MaterialsMaterials

Plant “muscle”

Plant muscle – a chemohydraulic system with 10 – 100 micron cell actuators

Cross-section of a Graminea leaf.

•• Distribute Distribute the the power power of of a a hydraulichydraulic actuation actuation system system into into materialsmaterials to to enable enable real real adaptive adaptive structures.structures. •• 5-80% 5-80% strain, strain, 1-100 1-100 MPa MPa blockedblocked stress, stress, and and frequencies frequencies of 0.1 – 20 Hz. of 0.1 – 20 Hz. The Nastic material will have structure over 9 orders of magnitude and will require complementary fabrication techniques. SelfSelf--DecontaminatingDecontaminating SurfacesSurfaces

Surface localized biocidal coatings that are self-cleaning • Renewable biocide • Poor adhesion of bacteria • Automatic removal of dead bacteria Self-cleaning

Capture • <0.1 wt% additive to not • Tailorable surface property deteriorate bulk properties Activate • Universal method • Germinate spores if necessary • Robust Kill • Bacteria, spores and viruses Surface Localization Biocide Capture, Activate, Kill Enhanced System Performance

Biomimetic Locomotion Biomimetic Sensing

Melanophila

Protein Thermal Sensor

Fish Eye

LocomotionLocomotion inin Unplanned,Unplanned, RoughRough TerrainTerrain forfor DeniedDenied AccessAccess OperationsOperations BioroboticsBiorobotics –– WhatWhat’’ss NextNext

STEEP, LOOSE ENVIRONMENT

COMPLIANT MANIPULATION

VERTICAL MOBILITY BioBio--InspiredInspired OpticsOptics DemonstrationsDemonstrations

Fluidic Zoom Lens Liquid Crystal Foveated Imaging Pointer UAV No zoom 30X zoom 30 degrees by 22 degrees FOV f=1.8 100g 0.8 0.7 UCF-S3 0.6 16-162 °C 0.5

0.4 PDMS 0.3

Fluid Birefringence Birefringence 0.2 Glass 0.1 State of the Art

Dragon Eye UAV 0 BL 038 (Merck) 20 40 60 80 100 120 140 160 180 Fixed FOV (80 degrees) Variable FOV (90 to 180 degrees) Temperature (°C) 10g f=1.5. Dynamic Grin Lens

36nm

PC PMMA Infrared/ThermalInfrared/Thermal SensingSensing

• Melanophila acuminata pit organ triggers photomechanical reaction upon absorption of mid-IR radiation (~ 3 µm) • Outer membrane expands ~ 1 nm to trigger mechanoreceptor

• Common theme mechanistically: photon absorption mechanical energy

Infrared Pit Organ 10 µm BiomimeticBiomimetic ThermalThermal ArrayArray “The primary weapons system of the US Special Operations Command is the trained, cognitive, independently operating human being. …We must significantly enhance the human dimension.”

ViceVice AdmiralAdmiral EricEric OlsonOlson DeputyDeputy CommanderCommander SOCOMSOCOM MarchMarch 20042004 BiomedicalBiomedical ThemesThemes

• Maintain peak physical and cognitive performance to avoid becoming a casualty. • Diagnose disease and/or vulnerability as early as possible, even before symptoms. • Redefine acute battlefield diagnostics and therapeutics to assure survival. • Revolutionize convalescent care to guarantee healing and return of normal function. LonLongg TermTerm StoraStoraggee ofof BloodBlood ProductsProducts

BloodBlood PlateletsPlatelets:: ProgramProgram Achievement:Achievement: essentialessential forfor clottingclotting andand StorageStorage forfor 22 yearsyears at at roomroom healing.healing. temperaturetemperature,, withwith CurrentCurrent Storage:Storage:5 5 days,days, maintenancemaintenance ofof normalnormal refrigeratedrefrigerated,, constantconstant function.function. mixing.mixing. dem tIno vivoaffActivityord in Rehydrated Platelets eteRelative increase ofcalcium flux(%) protection120 • Clotting activity 100 man cells demonstrated in 80

experimental animals. 60 Fresh Rehydrated • Clinical development plan 40 ongoing with FDA and 20

WRAIR. 0 0.0 0.2 0.4 0.6 0.8 1.0 Thrombin (U/ml)

Continuing Efforts : Red Blood Cells • 70% viable following desiccation. • Expect 95% viability with new methods. Maintaining Soldier Combat Performance Cognitive Task • Preventing Sleep Deprivation 100 Delayed Match -to-Sample – Prevent the degradation of cognitive performance caused by sleep deprivation 80 Percent Correct – Judgment and memory errors put troops into harms way 60 – Current approaches (amphetamines, etc) do not improve cognition! 40 Baseline 20 Sleep Deprived (36 Hours) • Soldier Self-Care Sleep Deprived + Ampakine – Reduce reliance on a fixed infrastructure of 0 1-5 6-10 11-15 16-20 21-25 26-30 medical care Delay (sec) – Evacuation takes hours – past golden hour – Pain and bleeding prevent soldiers from protecting • Peak Soldier Performance themselves – Controlling metabolism, thermophysiology,

10 reecovery and maintenance – Can’t get enough calories! (loss of weight up 8 to 30 pounds) – Lack of energy 6 – Immune deficient

2 Cumulative resting pain score score pain pain resting resting Cumulative Cumulative

0 untreated RI624 Morphine RI624 + Morphine PreventingPreventing SleepSleep DeprivationDeprivation

AmpakinesAmpakines-- a a classclass ofof AmpakineRestores medicationsmedications that:that: 100 Performance to Baseline --enhanceenhance nervenerve signalssignals 80 Percent Correct --areare provenproven safesafe inin 60 humanshumans --areare currentlycurrently inin clinicalclinical 40 trialstrials forfor dementiadementia Baseline 20 Sleep Deprived (36 Hours) Sleep Deprived +Ampakine 0 1-5 6-10 11-15 16-20 21-25 26-30 Delay (sec)

FlavenolsFlavenols:: aa naturalnatural anti-anti- oxidantoxidant compoundcompound inin chocolatechocolate -- protects protects againstagainst nervenerve cellcell injury.injury.

Neurogenesis Soldier Self-Care

Pain Mitigation Equivalent to Morphine Demonstrated

8 Reduced Pain

2 Cumulative resting pain score score pain pain resting resting Cumulative Cumulative

0 untreatedUntreated AntibodyRI624 MorphineMorphine HeatHeat ExtractionExtraction

CoolingCooling Between Between Exercise Exercise Sets Sets Improved Improved PerformancePerformance of of Special Special Forces Forces Personnel Personnel by by an an AverageAverage of of 20% 20% ““VirtualVirtual”” SoldierSoldier

• A “Virtual” Representation of Anatomy, Physiology, and Biochemistry That Would Allow Instant and Automatic Diagnosis and Triage of an Internal Combat Injury • Increase heart wound diagnosis by 80% System Brain Muscle Heart Lung Kidney Liver

System

Organ

Tissue Level Physiology

Cellular

BioChem

Gene Enhanced Survival and Recovery

Surviving Blood Loss Restorative Injury Repair

• Drastically reduce the metabolic • Changing the nature of repair from (oxygen) demand of organs and cover to function organisms, i.e., “stasis”on demand for periods, initially, of up to 6 hours • Natural Mechanisms • Preconditioning RestorativeRestorative InjuryInjury RepairRepair

Wound Closure vs. Wound Closure vs. Wound Environment RestorativeRestorative Injury Injury Repair Repair Pluripotent Cell Recruitment Controlled Organization Open Epidermis Defect TODAY Dermis FUTURE Clot Muscle Traumatic Tissue Loss with clot formation

Fibrotic Repair Response Blastemic Repair Response

Basement Epidermis Epidermis Membrane Granulation Dermis Blastema Lack of Dermis Tissue Basement Membrane Muscle Muscle Response with Inflammatory & Fibrotic Cells Response with Dedifferentiated Local Cells and Infiltrating Stem Cells

Morphogenesis

Basement Epidermis Basement Epidermis Membrane Membrane Scar Dermis Dermis Muscle Muscle

Repair with Scar and Loss of Function Return of form and function Cognitive Behavior and Understanding

Training Superiority Rapid Checkpoint Screening • A peaceful military continuously at “virtual” war • Unintended consequence of transformation: everybody must think

12/1 USN

10/1

Navy Fighter 8/1 Weapons (Top Gun) School 6/1 • Measure brain/body function 4/1 to identify exploitable signals Air-to-Air Combat Exchange Ratio Exchange Ratio Air-to-AirAir-to-Air Combat Combat EnemyEnemy Losses Losses / U.S./ U.S. LossesLosses USN USAF to understand deception 2/1 no one USAF shot down on either detection side in 1969

1965-1968 1969 1970-1973 TheThe DARPADARPA GrandGrand ChallengeChallenge

The best 200+ miles of $1 million cash autonomous some of the prize robotic vehicles toughest terrain America can in the world 13 March 2004 build Winner takes all Grand Challenge – March 13, 2004 Winding,Winding, NonNon--SurfacedSurfaced RoadsRoads WaterWater ObstaclesObstacles