BRITTON CHANCE

Department of Biochemistry/Biophysics

ICAS Annual Liberty Award Presentation7:30-9:00 PM, December 14, 2005

Science and My LifeScience and My Life

(07/24/1913 ~ )

My First Invention:My First Invention:Compass Controlled Automatic Ship SteeringCompass Controlled Automatic Ship Steering

Photo Sensor with Negative FeedbackPhoto Sensor with Negative Feedback

(1931-1938)(1931-1938)

Automatic Ship Steering – Texas SunAutomatic Ship Steering – Texas Sun

The first optical sensor from magnetic compass The first optical sensor from magnetic compass

Compass

45 o mirror

Prisms

Photocells

(1937)(1937)

US Patents: 2228199, 2228200, 2102511, 2102512, 2102513, 2132676, 2132677, 2182696, 2182717, 2185074, 2289242, 2337589

The Enzyme-Substrate Compounds The Enzyme-Substrate Compounds and Stopped Flow Apparatusand Stopped Flow Apparatus

Cambridge UniversityCambridge UniversityTrinity CollegeTrinity CollegePhysiology LabPhysiology Lab

(1938-1941)(1938-1941)

Manually driven syringes

Original Stopped Flow Apparatus made by hand in the Physiological laboratory, Cambridge University FJW Roughton and GA Millikan supervisors of Ph.D. study on enzyme kinetics.

Time range to 0.3 msec and k1 107 M-1sec-1

Lucite mixer made by hand with dental drills

Strings!

Stopped Flow ApparatusStopped Flow Apparatus

Mechanical Differential Analyzer for Solutions of Non-linear Differential Equations for Enzyme Action

(1936~1937) UPenn Moore School, JG Brainerd

Computer Fit (Solid Line) to the Experimental Kinetics of Product of Formation fromEnzyme-Substrate Compound (1939)

Computer Fit (Solid Line) to the Experimental Kinetics of Product of Formation fromEnzyme-Substrate Compound (1939)

Product FormationKinetics of Enzyme-

Substrate Compound

620 nm430-405 nm

pkkpexkdt

dp)()( 321 pkpexk

dt

dx21 )(

The Radar WarThe Radar War (1941-1946) (1941-1946)

MIT Radar Lab Group 63MIT Radar Lab Group 63Precision Timing and Computing CircuitsPrecision Timing and Computing Circuits

SCR-584, SG-3, APA-44, APQ-13, APS-15SCR-584, SG-3, APA-44, APQ-13, APS-15Long Range Navigation (LORAN)Long Range Navigation (LORAN)

The Radiation Laboratory Steering Committee The Radiation Laboratory Steering Committee ““The Brain Trust” (1943)The Brain Trust” (1943)

Steering committee not shown in the picture: Purcell, Pound, Ramsay, Schwinger, Alvarez and others.

RabiPollard

Bonner

Zacharias Haworth

Herb Marshall

Ridenour

DubridgeEwing

LawsonGetting

LoomisChance

Elevation Potentiometer

Oil LevelPlug

Oil DrainPlug

Selsyn Compartment

Slip-ring Compartment

Canvas Drain Duct

Elevation Drive Motor

Elevation Gear Housing

Elevation Selsyn Housing

SCR-584SCR-584Radar Lab antiaircraft 10 cm autotracking Radar directly coupled to Bell Labs electronic computer and 5” hydraulically controlled guns.

Action at Anzio, Normandy and Buzzbombs.

Back to BiochemistryBack to BiochemistryVia Stockholm and Cambridge Via Stockholm and Cambridge

Guggenheim FellowGuggenheim Fellow(with Hugo Theorell and David Keilin)(with Hugo Theorell and David Keilin)

Mitochondrial and Tissue SpectroscopyMitochondrial and Tissue Spectroscopy

(1947-1951) (1947-1951)

Olympic GamesOlympic Games(1952)(1952)

Training for Helsinki OlympicsTraining for Helsinki Olympics

Sandhamn, SwedenJuly 1952

Olympic Medal Helsinki 1952Olympic Medal Helsinki 1952

Gold MedalGold Medal

BC at Helm of Complex IIIBC at Helm of Complex III

The first USSR world championship, Tallin, Esthonia 1962 First Place

More Adventures in ScienceMore Adventures in ScienceDual Wavelength SpectroscopyDual Wavelength Spectroscopy

Time Shared Dual Wavelength Spectrophotometer Time Shared Dual Wavelength Spectrophotometer for Turbid Mitochondrial Suspensionsfor Turbid Mitochondrial Suspensions

MonochromatorSet to A

MonochromatorSet to B

Exit slit

60Hz Vibrating mirror

Half silvered mirror

Sample

Photomultiplier

Light Source

Exit slit

Entrance slit

Respiration Chain: Respiration Chain: Mitochondria cytochromes flavins and Pyridine nucleotides Reduced minus oxidized spectrumMitochondria cytochromes flavins and Pyridine nucleotides Reduced minus oxidized spectrum

with Ron Williamswith Ron Williams

Keilin’s Cytochromes

Fluorescent NADH and Flavoprotein

NADH Fp Q b c1 c a a3 O2 Oxygen Sensor (10-8M)

Mitochondrial Function: Fast Response to Energy Demand and Calcium Transport

with Maria Erecinska

Mitochondrial Function: Fast Response to Energy Demand and Calcium Transport

with Maria Erecinska

ADP Ca++

Intraoperating Flying Spot Scan of mitochondrial flavoprotein fluorescence on exposed Human Brain

STA-MCA Anastomosis (1960)with George Austin

Intraoperating Flying Spot Scan of mitochondrial flavoprotein fluorescence on exposed Human Brain

STA-MCA Anastomosis (1960)with George Austin

BC-X 202

Fp Oxidized

Quantum Mechanical Electron Tunneling Quantum Mechanical Electron Tunneling in the Photosynthetic Reaction Centerin the Photosynthetic Reaction Center

with Don DeVaultwith Don DeVault(1960-1970)(1960-1970)

DeVault, D. and Chance, B. (1966) Biophys J 6(6):825-847

General arrangement of the apparatus for photosynthesis with laser pulses. The reactions are followed spectrophotometrically with monochromator photomultiplier and oscilloscope.

Laser Apparatus for Electron Tunnelling Discovery and in Chromatium

Low Temperature Electron Tunnelling: Cytochrome Oxidation at 77K

Low Temperature Electron Tunnelling: Cytochrome Oxidation at 77K

DeVault, D. and Chance, B. (1966) Biophys J 6(6):825-847

.

Our Preliminary Tunnelling MechanismOur Preliminary Tunnelling Mechanism

DeVault, D. and Chance, B. (1966) Biophys J 6(6):825-847

Muscle BioenergeticsMuscle Bioenergetics

MRS of Human LimbsMRS of Human Limbs

(1982 onwards)(1982 onwards)

In Magnet ExerciseIn Magnet Exercisewith Jack Leighwith Jack Leigh

Muscle BioenergeticsMuscle Bioenergetics

MRS of Human LimbsMRS of Human Limbs

(1982 onwards)(1982 onwards)

In Magnet ExerciseIn Magnet Exercisewith Jack Leighwith Jack Leigh

BC’s Leg in 1.5T MagnetFirst MRS of Human (1982)

BC’s Leg in 1.5T MagnetFirst MRS of Human (1982)

BC’s head in 13 kilogauss magnet First Head in Magnet (1982)

BC’s head in 13 kilogauss magnet First Head in Magnet (1982)

Model: Mayonnaise

A New ChapterA New ChapterClinical NIR Imaging: Brain Optical ImagingClinical NIR Imaging: Brain Optical Imaging

(OISO 1996)(OISO 1996)

A New ChapterA New ChapterClinical NIR Imaging: Brain Optical ImagingClinical NIR Imaging: Brain Optical Imaging

(OISO 1996)(OISO 1996)

In order to provide a faster, cheaper, portable brain imager, we turn to NIR spectroscopy and imaging.

Lower resolution but more biochemistry!

With Qingming LuoWith Qingming Luo

Model for coupling of synaptic activity with glucose utilization.Adapted from Magistretti, P.J., et al (Oct. 1999) NIPS 14: 177-182

At glutamatergic synapses, the action of glutamate is terminated by an efficient glutamate uptake system located in astrocytes (1). Glutamate is cotransported with Na+, resulting in an increase in the intracellular concentration of Na+, leading to the activation of the Na+-K-ATPase (2a). Glutamate is converted to glutamine by glutamine synthase. (2b) Activation of the Na+-K+-ATPase triggers aerobic glycolysis (3). Lactate produced by the glutamate-stimulated glycolysis is released from astrocytes (4). A. synatic activation; B, direct glucose uptake into neurons under basal conditions. Pyr, pyruvate; Lac, lactate; Gln, glutamine; G, G protein; PGK, phosphoglycerate kinase. Copyright (1994) National Academy of Sciences, USA

O2 Utilization

Synaptic JunctionCyanide Sensitive

Astrocyte Cyanide Insensitive

Capillary

Capillary

O2 Glucose

Arachnoid space

Pia matter (< 1 mm)White matter

Brain cortex(4 mm)

Skull(4-6 mm)

At a fixed separation of sources (4) and detectors (16), the functionally activated signal cause absorption changes according to Beers Law from whcih incremental changes of total hemoglobin (HbT) oxy-deoxy hemoglobin are computed:∆CHbT = ∆OD805 / ∆805 X

L

Where ∆E is the incremental absorption coefficient, ∆OD the absorbance changes in functional activity and L is the photon migration pathlength and saturation of Hb can be computed:

Spectroscopy and Imaging of Human Brain Cortex

HbO2∆Y = HbO2+Hb=

HbO2+Hb1

1+Hb

HbO2

“oxy” Differential x(850) - y(760)“BV” single ended z(805)

Minimize “oxy” and “BV” crosstalk by adjusting x, y on blood model system

Wavelength Selection Blood -Lipid Model 40 M HbO2

G.A. Millikan (1935) B. Chance (1951)

Dual wavelength measurement of saturation and rejection of blood volume changes

Dual wavelength measurement of saturation and rejection of blood volume changes

BC 368d

JDu 1

Multi Source Multi Detector NIR ImagerThree Wavelength Time Multiplex 16-Channel NIR Imager

Multi Source Multi Detector NIR ImagerThree Wavelength Time Multiplex 16-Channel NIR Imager

BC 423

The optical detector of brain function is easily held in place over forehead with Velcro straps

The optical detector of brain function is easily held in place over forehead with Velcro straps

Cognitive Function: Anagram Solutions

16 Detector NIR Imager

(1996 to date)With S Nioka

NIR PFC Images Brodman's 9&10

Cognitive Function: Anagram Solutions

16 Detector NIR Imager

(1996 to date)With S Nioka

NIR PFC Images Brodman's 9&10

Display of histograms for 16 pixels in ~700 anagrams solutions

Abscissa: signal strength (blood volume, 1M)Ordinate: number of trials (700)Projected onto the prefrontal cortex Brodman’s 9 & 10.

Sudden Insight Image NIR “Cognoscope” (EK)

Color representation of mean value of Gaussian fit to histograms

Are prefrontal “societal inhibitions” Are prefrontal “societal inhibitions” activated in falsehood?activated in falsehood?

Can the deceitful forebrain Can the deceitful forebrain be detected?be detected?

Coll: Drs. Ruben Gur, Dan LanglebenColl: Drs. Ruben Gur, Dan Langleben

Illustrating oxygenation changes due to false answers to sensitive questions (Subject A)

M=600 tests

SummarySummary

A pleasant trip through a number of adventures on the road to discovery and competitive achievements in science and sailing.

Collaborators - University of PennsylvaniaCollaborators - University of Pennsylvania

Shoko NiokaBaruch Ben-DorTao AoPing HuangGwen Lech Zhongyao Zhao Bleu ZhongJun Zhang Juan Du Xiaohong Li Walid M. Fahssi Ulas Sunar Bien Chu Gerald Mullin Chilton Alter

Center for Biomedical Optics Physics Dept.Arjun Yodh

Radiology Dept.J.S. LeighMitchell SchnallJerry Glickson Gang Zheng

Neurology Dept.William Bank

Chemistry Dept.Al GerwitzPonzy Lu

Children’s HospitalTony Simon

Lanlan ZhouCindy Wang Gunay YurtseverSammy ShanYe XingBarry John-Chuan David R. Busch Mahsa RanjiJoohee Im Dan Huang Yingting LiuXiang Cao Hui Sun

NTROIWafik S. El-Deiry

BioengineeringJohn Schotland

Collaborators - ElsewhereCollaborators - ElsewhereBruce TrombergU.C. Irvine, CA

Nimmi RamanujamUniv. of Wisconsin, Madison, WI

Michael PattersonHamilton, Ontario, Canada

Eva Sevick-MuracaTAMU, College Station, TX

Hanli LiuUniv. of Texas, Arlington, TX

Ken RundellOlympic Center, Lace Placid, NY

Sam AchilefuUniv. of Washington, St. Louis, MO

Maria DelivoriaEnla AndayMedical College of PAPhiladelphia, PA

Ralph Weissleder MGH, Boston, MA

Susan BriestLeipzig, Germany

Kevin McCullyUniv. of GeorgiaAthens, GA

Takafumi HamaokaToyko, Japan

H. KoizumiHitachi, Tokyo, Japan

Maria Anglina FranchesciniMGH, Boston, MA

Christopher H. ContagNTROI, Stanford

Ching H. Tung MGH, Boston, MA