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Finding the Sweet Spot in BioTechology
Russell G. Higbee, Ph.D., D.V.M.VaxDesign Corporation2721 Discovery Drive
Orlando, FL 32826www.vaxdesign.com
From Cells to Engineering to Automation to Products
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What’s gonna be the next technological revolution?R
&D
gro
wth
rat
e
Year1850 1900 1950 2000 20501800
steel Al plasticsmicro-
electronics
Nano-science?
TE
CH
NO
LO
GY
DE
VE
LO
PME
NT
TIME (year)2000 BC2000 BC 00 2000 AD2000 AD190019001800180015001500
CONSUMER ACCEPTANCECONSUMER ACCEPTANCE
AGRICULTURAL AGE
AGRICULTURAL AGE
INDUSTRIAL AGEINDUSTRIAL AGE
BIO-
, NAN
O-AG
E?
BIO-
, NAN
O-AG
E?
INFORM
ATION A
GE
INFORM
ATION A
GE
biotech
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Telegraph1838
Television1923
Personal Computer
1977
Radio1907
Wireless1895
Telephone1876
Communication Satellite
1958
Radar1936
Computer1941
1600 1800 20001700
Digital biology?
Can Anything be Learned or Predicted from Prior Inventions?
1600
1900
1800 1900 20001700
Distributed bio-power, Teleportation?Locomotive
1802Submarine
1624
Automobile1889
Helicopter1940
Jet1928
Steamship1807
Airplane1907
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World Economic Performance Was Sparked by “One” Event
GDP Per Capita in Western Europe,1000 – 1999 A.D.
This curve looks quite smooth on a macroscopic scale.
Notice the “knee of the curve” occurs at the industrial revolution, circa 1850.
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Anesthesia1834
Vaccination1796 Penicillin
1928
Aspirin1853
1600 1800 20001700
Personalized medicine, cure for common cold, herbal medicine, broad-range immunotherapies, body parts on demand?
Can Anything be Learned or Predicted from Prior Inventions?
1900
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• Industrial revolution was an amalgam of ideas aboutmachines to manufacture or to move quickly on the earth.
• Flood of ideas in the 19th century, but none would havebeen realized without Watt’s steam engine.
• The internal combustion engine made the 20th century industrial revolution continue (Brayton, Otto)
• Has there been that one good concept to make a difference in biotech? (tissue engineering, recombinant DNA technology, self-assembly, stem cells, nanoscience, …)
One Good Idea Makes the Difference
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The Future: Amalgascience -Coordination With Other Disciplines
Bio SensorsBio Sensors
MicroelectronicsMicroelectronics
Micro-robotsMicro-robots
BioInformaticsBioInformatics
Stem CellsStem Cells
Bio
Tech
nolo
gyB
ioTe
chno
logy
InformationInformationPhysi
cal s
cience
s
Physica
l scie
nces
ImmunologyImmunology
Living MachinesLiving Machines
Particle physicsParticle physics
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Biotech/Tissue Engineering Opportunities
Cure: creation of neo-organs in vivo
Diagnostics: artificial immune system
Detect: rare event imaging
(a) Low-Intensity UV Pulses (b) Fluorescence Detection (c) Laser Ablation
(d) Material Removal (e) Saline Flush Removal (f) Deposition
Interaction statistics: digital biology
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The Question...
How can one, short of reproduction, reproducibly build a biocompatible structure that replicates
the natural living system (microenvironment, 3D structure, vascularization, etc.) to support normal
cell development?
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Part of the Answer: Tissue Engineering
http://www.pittsburgh-tissue.net/about_te/index.html
Problems:• Largely 2D• No cellular, biomolecule nor biomaterial geospatial control• No “zone” control in the z direction• No customizationTherefore – hard to replicate the endogenous tissue
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Utilize fundamental advancements in minimally invasive surgery [MIS], tissue
engineering, and digital printing CAD/CAM techniques to create customized
body parts by allowing the surgeon to build tissues from within
InVivo Biological Architectural Tool
Physics issues:• Fine deposition• Nozzle design• Actuation (macro to micro)• Motor control• Fiber coupling fsec laser
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Why Body Parts on Demand?
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Various Printing Demonstrations:
Physics issues:• Nozzle shear forces• Mat’ls issues to build 3D structures• Vision, imaging, feedback, & motion control
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Fractal Painting The Man Direct-Painting
ART to Tissue Engineered PART
Truly Going from ART to PART
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10 fs light pulse
10-14 10-9 10-4 101 106 1011 1016
Age of universe
Time (seconds)
1 minute
Pentium clock cycleCamera flash Age of USA
One month
Femtosecond Time-Scales:
Ultra-Short Pulse Lasers
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Laser Micromachining/Surgery
Nanosecond machiningFemtosecond machining
Micromachining on paper
Physics Issues:•Waveguide designs•Bending losses•Diffractive optics
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Cure: creation of neo-organs in vivo
Prevent: artificial immune system
Detect: rare event imaging
Interaction statistics: digital biology
Biotech/Tissue Engineering Opportunities
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The Costs to Bring Immunotherapies to the Market
• High risk• Large investment• Ill-afford lost opportunity costs
http://www.vaccinealliance.org/site_repository/resources/21VacMarket.pdf
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1. Why it costs so much to bring drugs to the market?• Animals lie and exaggerate• Lost opportunity costs
2. How can you make money by accelerating the drug development process?• Find the bottleneck & turn the
problem inside out• Create in vitro surrogate human
immune systems
Challenging Disease and the Market Differently
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0
500
1000
1500
2000
2500
Low Mid High
HBsAg ELISA Titers
Relative HBsAg EIA titer
N=5
N=10; Max titer
N=6
0
200
400
600
800
1000
Low Mid High
LTE ELIspot
ASC
/106 h
arve
sted
B c
ells
Relative HBsAg EIA titer
N=5
N=10
N=6
Serum titer groupings: Low 3-57.1; Mid 128-864; High 2000 or > 2000
ELIS
A Ti
ter
Correlative Analysis of AIS Response vsSerum Titer for Hepatitis B
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Designing an In Vitro Biological System
• How to mimic biology- don’t give into the biologists- don’t make it too simple- the right cells @ the right time @ the right place
• How to assemble biology- self-assembly- synthetic assembly- forced assembly
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Self-Assembly of the Germinal Center
In vitro GCSchematic representation of a GC
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Synthetic Assembly of a Germinal Center
T cell motility
-CCL21 +CCL210
10
20
30
40
50
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“Forced” Assembly
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Cure: creation of neo-organs in vivo
Prevent: artificial immune system
Detect: rare event imaging
Interaction statistics: digital biology
Biotech/Tissue Engineering Opportunities
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The 3D structure of the ligand molecule, e.g. an antigen (agonist) matches the 3D structure of the antibody (receptor). This physical contact induces the cell function.
Challenge the Antigen/Antibody Physical Contact Model
http://www.emc.maricopa.edu/faculty/farabee/biobk/antigenAB.gif
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Physical Contact ModelSpecific molecular interactions happen after random
collisions between partners on a trial-and-error basis, using electrostatic, short range (two to three times the molecule size) forces.
But this kind of random encounter, amidst the bulk of molecules which are foreign to a given biochemical reaction, would give to these meetings statistically little chance of occurring.
Thus, the simplest biological event might require a very long time to happen. This paradox is still unexplained by those adhering to this theory...
www.digibio.com
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Short Range Interactions Do Not Satisfyi.e, they are all “wet”
SS DNA and its complement act like psuedo “glue”
Tom Mallouk, Penn State University
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Small changes in the spectrum of a molecule (e.g. induced by a tiny structural change) would profoundly alter its resonating characteristics
Minute changes radically modify the molecular tertiary structure and function.
• phosphorylation,• replacement of an ion by a similar one, • switching of two peptides, • 1 to 4 amino acid substitutions within HA can give rise to new viral strains
If Not Physical Contact Alone, Could Electromagnetics Come to the Rescue?
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Cure: creation of neo-organs in vivo
Prevent: artificial immune system
Detect: rare event imaging
Interaction statistics: digital biology
Biotech/Tissue Engineering Opportunities
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Going from Science to Business(1) building in vitro models & diagnositics, which will not require FDA
approval
(2) manufacturing of the AIS constructs will occur via more automated processes in a cost effective manner
96 well formatautomatedcost-effectivesimple manufacturing
(3) the targeted market segments are the vaccine, cosmetics, bigpharma, and chemical industries which are significantly larger and have deeper pockets than that of the burn and wound healing markets
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Sometimes You Have To Think Differently – Turn the Problem Upside Down
Technical community is working on• in vitro bioreactors• in vivo/FDA approval• stopping an immune reaction• animal studies• expensive nanoscience• manual processes• centralized distribution• experts
A better approach is • in vivo bioreactor (human)• in vitro models• inducing an immune response• using surrogate models• duct tape, ebay, • automated processes• distributed processes• nature
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This work was funded by DARPA/DSO in the Rapid Vaccine Assessment Program