Crucible of Science This page intentionally left blank Crucible of Science THE STORY OF THE CORI LABORATORY JOHN H. EXTON 3 3 Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With offi ces in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Th ailand Turkey Ukraine Vietnam Oxford is a registered trademark of Oxford University Press in the UK and certain other countries. Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016 © Oxford University Press 2013 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitt ed, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitt ed by law, by license, or under terms agreed with the appropriate reproduction rights organization. Inquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above. You must not circulate this work in any other form and you must impose this same condition on any acquirer. CIP data is on fi le at the Library of Congress ISBN 978–0–19–986107–1 9 8 7 6 5 4 3 2 1 Printed in the United States of America on acid-free paper Dedicated to Charles Rawlinson (Rollo) Park This page intentionally left blank Contents Acknowledgments ix I n t r o d u c t i o n xi 1. Carl and Gerty Cori: Early Life 1 2. Sidney Colowick: Their First Graduate Student 16 3. Herman Kalckar: The Great Dane 21 4. Severo Ochoa: Spanish Genius 29 5. Move to Enzymology and Work of Arda Green 39 6. Luis Leloir: One of Argentina’s Greatest Scientists 45 7. Earl Sutherland: Master of Intuition 53 8. Coris’ Move to the Department of Biological Chemistry: Award of Nobel Prizes and Career of Tom Cori 67 9. Sidney Velick: Modest Enzymologist 73 10. Victor Najjar: Pediatrician and Immunochemist 78 11. Edwin Krebs: Accidental Biochemist 82 12. Mildred Cohn: Against All Odds 91 vii viii Contents 13. Christian de Duve: Belgian with Savoir Faire 100 14. Arthur Kornberg: A Giant of Biochemistry 112 15. Hormone Effects on Muscle Carbohydrate Metabolism 123 16. Charles Park: Aristocratic Physiologist 127 17. Jane Harting Park: Enthusiast for Science 139 18. Gerty Cori’s Work on Glycogen Structure and Glycogen Storage Diseases 145 19. Joseph Larner: Focus on Glycogen Synthase 149 20. Contributions of Barbara and David Brown 161 21. William Daughaday: All About Growth 165 22. Robert Crane: A Decade with Carl Cori 171 23. Alberto Sols: Spanish Enzymologist 176 24. Luis Glaser: The Complexity of Carbohydrates 181 25. Ernst Helmreich: Jovial Bavarian 189 26. Carl Frieden: Enzyme Kineticist 196 27. David Kipnis: Focus on Diabetes 201 28. William Danforth: Academic Leader 206 29. The Infl uence of the Coris on Washington University and Carl Cori’s Research at Boston 210 30. The Heritage of the Coris 214 I n d e x 221 Acknowledgments Regrett ably, many of the scientists who worked in the Cori laboratory have passed on and I have had to depend on writt en sources to reconstruct their lives and accomplishments. However, I am grateful to some of them who are still active and have great recollections of the laboratory. In this regard, I would like to thank Rollo and Janey Park, Joe Larner, Ernst Helmreich, Barbara (Bobbie) and David Brown, Luis Glaser, and Carl Frieden. I was also greatly helped by conversations with Maryda Colowick, Jennifer and Tilly Najjar, Tom Cori, Joel Hardman, and Murray Heimberg. No work of this magnitude can be accomplished without the assistance of many people. Th us I would particularly like to thank Jeremy Lewis and Hallie Stebbins my editors at Oxford University Press, and Maureen Cirnitski for superb copyediting. I am particularly grateful to Phil Skroska, Archivist, Visual and Graphic Archives at the Bernard Becker Medical Library at Washington University. Other important people were James Th weatt and Christopher Ryland of the Special Collections, Eskind Biomedical Library, Dominic Doyle of the Medical Art Group; and Kevin Davis of the General Counsel, all of Vanderbilt University. Others who provided help at vari- ous stages were Douglas Atkins of the National Library of Medicine, Louis Hue and Monique Van de Maelen at the de Duve Institute, Brussels. An important contribu- tor to the book was my Vanderbilt colleague Owen McGuinness, who provided much-needed word processing skills. Finally, but not least, I thank my wife Janet for her continuous support during the longer than expected birth of this book. ix This page intentionally left blank Introduction Th is is the story of Carl and Gerty Cori who established a laboratory at Washington University in St. Louis, Missouri, when Carl was appointed chair of Pharmacology in 1931 and chair of Biological Chemistry in 1946. Th e Cori labo- ratory remains unique in its contributions to biomedical science. Not only did both the Coris win the Nobel Prize, but also six other Nobel Laureates emerged from their laboratory, a record unmatched by any other U.S. institution. Th e dis- coveries of the Coris and their associates led to great advances in knowledge of how the body controls the level of glucose in the blood and how insulin and other hormones aff ect this. They defi ned the mechanisms by which the hormones epi- nephrine and glucagon control the breakdown of glycogen, which is the storage form of glucose in the body. Th ey studied the uptake of glucose from the gut and tracked what happened to it in the body. Th ey identifi ed many of the reactions involved in the processing of glucose and glycogen in the body and characterized many of the enzymes catalyzing these reactions. Th ey also studied how glucose was taken up by muscle and how hormones infl uenced this. us,Th their investiga- tions into carbohydrate metabolism were of great relevance to normal physiol- ogy and metabolic diseases such as diabetes. Th e Coris were both born in Prague in 1896 and met at the same medical school there. Aft er service in the Austrian Army during World War I, Carl fi nished his clini- cal studies and went to Vienna to marry Gerty. Because of Gerty’s Jewish heritage and the general conditions of life in Europe at that time, they decided to emigrate to the United States in 1922 where they took positions at a cancer research insti- tute in Buff alo. Th is is where they carried out their classic studies of the eff ects of adrenaline on glucose and glycogen metabolism that led to the formulation of the Cori cycle. Th e Cori cycle is a metabolic cycle whereby lactic acid released into the bloodstream by the breakdown of glycogen in muscle is reconverted to glycogen in the liver, and glucose produced by the breakdown of glycogen in the liver is returned to the muscle. xi xii Introduction In 1931, Carl was surprised to receive an off er from Washington University in St. Louis to become chairman of Pharmacology. When they took up their appoint- ments, the Coris resolved that real advances in their fi eld of research would come from the use of isolated tissues and the purifi cation and characterization of the enzymes involved in glucose and glycogen metabolism. Th is decision profoundly aff ected the course of their research, and their laboratory at Washington University was soon recognized to be at the forefront of biochemical research in the United States. Even before the Coris received the Nobel Prize in 1947, young scientists fl ocked to their laboratory from all over the United States and the world. Th e Coris had rather formidable personalities and were rigorous and demanding mentors. Th ey were intolerant of sloppy thinking and emphasized that any projects should be truly novel and any data should be reproducible and internally consistent. Th ey insisted that data should be analyzed quantitatively where applicable and that results should not be interpreted in terms of any preconceived notions, but with due consideration of alternative explanations. In short, their laboratory provided a superb training in the scientifi c method. Many of the scientists that trained in the Cori laboratory went on to make major discoveries and to win Nobel Prizes (Figure 1), and the careers of many of these are described in this book. Notable among them was Herman Kalckar, a Dane with an exceptionally creative mind who made wide-ranging discoveries and interacted with an astonishing number of Nobel Laureates. He made many important contri- butions to biochemistry. Th e Coris’ fi rst graduate student was Sidney Colowick, who had never taken a course in biochemistry and was qualifi ed by the U.S. gov- ernment as a shrimp inspector! He turned out to be a very quick learner and was described by Kalckar as having a brilliant analytical mind and being wise beyond his years. His experimental expertise was instrumental in the Coris’ discoveries in St. Louis. A major fi nding in which he played a key role was to defi ne the product of phosphorylase action on glycogen, which was, unexpectedly, glucose-1-phosphate. Colowick later achieved fame as coeditor of Methods in Enzymology , a series of vol- umes popularly known as the biochemist’s bible.