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ICAS Annual Liberty Award Presentation 7:30-9:00 PM, December 14, 2005 Science and My Life BRITTON CHANCE (07/24/1913 ~ ) Department of Biochemistry/Biophysics My First Invention: Compass Controlled Automatic Ship Steering Photo Sensor with Negative Feedback (1931-1938) Automatic Ship Steering – Texas Sun The first optical sensor from magnetic compass (1937) 45 o mirror Compass Photocells Prisms US Patents: 2228199, 2228200, 2102511, 2102512, 2102513, 2132676, 2132677, 2182696, 2182717, 2185074, 2289242, 2337589 The Enzyme-Substrate Compounds and Stopped Flow Apparatus Cambridge University Trinity College Physiology Lab (1938-1941) Stopped Flow Apparatus 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 Strings! Lucite mixer made by hand with dental drills 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 from Enzyme-Substrate Compound (1939) dx k1 x(e p) k 2 p dt Product Formation 620 nm dp k1 x(e p) ( k 2 k 3 ) p dt Kinetics of EnzymeSubstrate Compound 430-405 nm The Radar War (1941-1946) MIT Radar Lab Group 63 Precision Timing and Computing Circuits SCR-584, SG-3, APA-44, APQ-13, APS-15 Long Range Navigation (LORAN) The Radiation Laboratory Steering Committee “The Brain Trust” (1943) Zacharias Herb Haworth Ewing Marshall Ridenour Bonner Rabi Dubridge Getting Lawson Chance Loomis Pollard Steering committee not shown in the picture: Purcell, Pound, Ramsay, Schwinger, Alvarez and others. SCR-584 Radar Lab antiaircraft 10 cm autotracking Radar directly coupled to Bell Labs electronic computer and 5” hydraulically controlled guns. Action at Anzio, Normandy and Buzzbombs. Elevation Selsyn Housing Elevation Potentiometer Elevation Drive Motor Oil Level Plug Oil Drain Plug Selsyn Compartment Elevation Gear Housing Canvas Drain Duct Slip-ring Compartment Back to Biochemistry Via Stockholm and Cambridge Guggenheim Fellow (with Hugo Theorell and David Keilin) Mitochondrial and Tissue Spectroscopy (1947-1951) Olympic Games (1952) Training for Helsinki Olympics Sandhamn, Sweden July 1952 Olympic Medal Helsinki 1952 Gold Medal BC at Helm of Complex III The first USSR world championship, Tallin, Esthonia 1962 First Place More Adventures in Science Dual Wavelength Spectroscopy Time Shared Dual Wavelength Spectrophotometer for Turbid Mitochondrial Suspensions Exit slit Monochromator Set to A 60Hz Vibrating mirror Sample Exit slit Monochromator Set to B Photomultiplier Entrance slit Light Source Half silvered mirror Respiration Chain: Mitochondria cytochromes flavins and Pyridine nucleotides Reduced minus oxidized spectrum with 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 ADP Ca++ Intraoperating Flying Spot Scan of mitochondrial flavoprotein fluorescence on exposed Human Brain STA-MCA Anastomosis (1960) with George Austin Fp Oxidized BC-X 202 Quantum Mechanical Electron Tunneling in the Photosynthetic Reaction Center with Don DeVault (1960-1970) Laser Apparatus for Electron Tunnelling Discovery and in Chromatium General arrangement of the apparatus for photosynthesis with laser pulses. The reactions are followed spectrophotometrically with monochromator photomultiplier and oscilloscope. DeVault, D. and Chance, B. (1966) Biophys J 6(6):825-847 Low Temperature Electron Tunnelling: Cytochrome Oxidation at 77K . DeVault, D. and Chance, B. (1966) Biophys J 6(6):825-847 Our Preliminary Tunnelling Mechanism DeVault, D. and Chance, B. (1966) Biophys J 6(6):825-847 Muscle Bioenergetics MRS of Human Limbs (1982 onwards) In Magnet Exercise with Jack Leigh BC’s Leg in 1.5T Magnet First MRS of Human (1982) BC’s head in 13 kilogauss magnet First Head in Magnet (1982) Model: Mayonnaise A New Chapter Clinical NIR Imaging: Brain Optical Imaging (OISO 1996) With Qingming Luo In order to provide a faster, cheaper, portable brain imager, we turn to NIR spectroscopy and imaging. Lower resolution but more biochemistry! Synaptic Junction Cyanide Sensitive O2 Utilization Astrocyte Cyanide Insensitive O2 Glucose Capillary Capillary Adapted from Magistretti, P.J., et al (Oct. 1999) NIPS 14: 177-182 Model for coupling of synaptic activity with glucose utilization. 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 Spectroscopy and Imaging of Human Brain Cortex White matter Pia matter (< 1 mm) Brain cortex Arachnoid space (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 / ∆E805 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: ∆Y = HbO2 = HbO2+Hb 1 Hb 1+ HbO2 Dual wavelength measurement of saturation and rejection of blood volume changes G.A. Millikan (1935) B. Chance (1951) Wavelength Selection Blood -Lipid Model 40 mM HbO2 BC 368d “oxy” Differential x(850) - y(760) “BV” single ended z(805) Minimize “oxy” and “BV” crosstalk by adjusting x, y on blood model system JDu 1 Multi Source Multi Detector NIR Imager Three 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 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, 1mM) 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 Can the deceitful forebrain be detected? Are prefrontal “societal inhibitions” activated in falsehood? Coll: Drs. Ruben Gur, Dan Langleben Illustrating oxygenation changes due to false answers to sensitive questions (Subject A) M=600 tests Summary A pleasant trip through a number of adventures on the road to discovery and competitive achievements in science and sailing. Collaborators - University of Pennsylvania Center for Biomedical Optics Shoko Nioka Baruch Ben-Dor Tao Ao Ping Huang Gwen Lech Zhongyao Zhao Bleu Zhong Jun Zhang Juan Du Xiaohong Li Walid M. Fahssi Ulas Sunar Bien Chu Gerald Mullin Chilton Alter Lanlan Zhou Cindy Wang Gunay Yurtsever Sammy Shan Ye Xing Barry John-Chuan David R. Busch Mahsa Ranji Joohee Im Dan Huang Yingting Liu Xiang Cao Hui Sun Bioengineering John Schotland Physics Dept. Arjun Yodh Radiology Dept. J.S. Leigh Mitchell Schnall Jerry Glickson Gang Zheng Neurology Dept. William Bank Chemistry Dept. Al Gerwitz Ponzy Lu Children’s Hospital Tony Simon NTROI Wafik S. El-Deiry Collaborators - Elsewhere Bruce Tromberg Ken Rundell Kevin McCully U.C. Irvine, CA Olympic Center, Lace Placid, NY Univ. of Georgia Athens, GA Nimmi Ramanujam Univ. of Wisconsin, Madison, WI Michael Patterson Sam Achilefu Univ. of Washington, St. Louis, MO Hamilton, Ontario, Canada Maria Delivoria Enla Anday Eva Sevick-Muraca Medical College of PA Philadelphia, PA TAMU, College Station, TX Takafumi Hamaoka Toyko, Japan H. Koizumi Hitachi, Tokyo, Japan Christopher H. Contag Ralph Weissleder Maria Anglina Franchescini NTROI, Stanford MGH, Boston, MA MGH, Boston, MA Hanli Liu Ching H. Tung Susan Briest Univ. of Texas, Arlington, TX MGH, Boston, MA Leipzig, Germany