1

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

2

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

3

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

4

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.

5

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

6

• 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

7

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

8

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

9

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?

10

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

11

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

12

Why Body Parts on Demand?

13

Various Printing Demonstrations:

Physics issues:• Nozzle shear forces• Mat’ls issues to build 3D structures• Vision, imaging, feedback, & motion control

14

Fractal Painting The Man Direct-Painting

ART to Tissue Engineered PART

Truly Going from ART to PART

15

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

16

Laser Micromachining/Surgery

Nanosecond machiningFemtosecond machining

Micromachining on paper

Physics Issues:•Waveguide designs•Bending losses•Diffractive optics

17

Cure: creation of neo-organs in vivo

Prevent: artificial immune system

Detect: rare event imaging

Interaction statistics: digital biology

Biotech/Tissue Engineering Opportunities

18

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

19

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

20

21

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

22

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

23

Self-Assembly of the Germinal Center

In vitro GCSchematic representation of a GC

24

Synthetic Assembly of a Germinal Center

T cell motility

-CCL21 +CCL210

10

20

30

40

50

25

“Forced” Assembly

26

Cure: creation of neo-organs in vivo

Prevent: artificial immune system

Detect: rare event imaging

Interaction statistics: digital biology

Biotech/Tissue Engineering Opportunities

27

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

28

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

29

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

30

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?

31

Cure: creation of neo-organs in vivo

Prevent: artificial immune system

Detect: rare event imaging

Interaction statistics: digital biology

Biotech/Tissue Engineering Opportunities

32

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

33

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

34

This work was funded by DARPA/DSO in the Rapid Vaccine Assessment Program