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Gary Zweiger transducing the genome This page intentionally left blank. transducing the genome INFORMATION, ANARCHY, AND REVOLUTION IN THE BIOMEDICAL SCIENCES Gary Zweiger McGraw-Hill New York • Chicago • San Francisco • Lisbon • London Madrid • Mexico City • Milan • New Delhi • San Juan Seoul • Singapore • Sydney • Toronto McGraw-Hill abc Copyright © 2001 by Gary Zweiger. All rights reserved. Manufactured in the United States of America. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, with- out the prior written permission of the publisher. 0-07-138133-3 The material in this eBook also appears in the print version of this title: 0-07-136980-5. All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw-Hill eBooks are available at special quantity discounts to use as premiums and sales pro- motions, or for use in corporate training programs. For more information, please contact George Hoare, Special Sales, at [email protected] or (212) 904-4069. TERMS OF USE This is a copyrighted work and The McGraw-Hill Companies, Inc. (“McGraw-Hill”) and its licensors reserve all rights in and to the work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hill’s prior consent. You may use the work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if you fail to comply with these terms. THE WORK IS PROVIDED “AS IS”. McGRAW-HILL AND ITS LICENSORS MAKE NO GUAR- ANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMA- TION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill and its licensors do not warrant or guarantee that the func- tions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill nor its licensors shall be liable to you or anyone else for any inac- curacy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of lia- bility shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise. DOI: 10.1036/0071381333 Contents Acknowledgments vii Introduction ix 1 Cancer, Computers, and a “List-Based” Biology 1 2 Information and Life 13 3 Behold the Gene 21 4 Working with Genes One at a Time 31 5 The Database 39 6 Getting the Genes 47 7 Prospecting for Genes with ESTs 61 8 ESTs, the Gene Race, and Moore’s Law 77 9 The End Game 87 10 Human Genome History 105 11 Comparing Human Genomes 117 12 A Paradigm in Peril 125 13 The Ancient Internet—Information Flow in Cells 135 14 Accessing the Information Output of the Genome 149 15 The Genomics Industry 161 16 The SNP Race 177 17 From Information to Knowledge 189 18 The Final Act 201 19 Future Prospects 207 Appendix: How the Patent Process Works 221 Glossary 235 Notes 239 Index 259 v Copyright 2001 Gary Zweiger. Click Here for Terms of Use. This page intentionally left blank. Acknowledgments Inspiration for writing this book came from numerous conversa- tions in which scientists and nonscientists alike expressed great interest in the human genome, the Human Genome Project, bio- informatics, gene patents, DNA chips, and other hallmarks of a new age in biology and medicine. There was a sense that history was being made and that biology, medicine, and even our concep- tion of ourselves would be forever changed. For some folks there was tremendous excitement over the possibilities and promises of genomics. For others there was trepidation and concern. However, nearly everyone I spoke with agreed that many of the history- making events and ideas were hidden from the public, and that scientists and general readers alike would benefit from the per- spective I had developed over the last decade. Many of the ideas and insights that I present here came through my work as a biologist in laboratories at Stanford University, Schering-Plough Corporation, Columbia University, and Genen- tech; in classrooms at various San Francisco Bay area community colleges; consulting for several different biotechnology investment groups; and through scientific, business, and legal work at Incyte Genomics and Agilent Technologies. This work brought me in con- tact with a vast network of people linked by the common goals of advancing our knowledge of life and improving human health, a perfectly primed source of help for a project such as this. Several pioneers in the genomics revolution graciously shared their recollections and insights with me. In particular, I thank John Weinstein of the U.S. National Cancer Institute; Leigh Anderson of Large Scale Biology; Leonard Augenlicht of Albert Einstein Uni- versity; Walter Gilbert of Harvard University; and Randy Scott, Jeff Seilhamer, and Roy Whitfield of Incyte Genomics. vii Copyright 2001 Gary Zweiger. Click Here for Terms of Use. viii ACKNOWLEDGMENTS I owe many thanks to coworkers at Incyte Genomics, who were both terrifically forthcoming in sharing their enthusiasm and ideas and tremendously supportive of my extracurricular activities. In particular, I wish to thank Jeanne Loring, Huijun Ring, Roland Somogyi, Stefanie Fuhrman, Tod Klingler, and Tim Johann. I am also especially grateful for the support of my coworkers at Agilent Technologies. In particular, I wish to thank Bill Buffington, Stuart Hwang, Mel Kronick, Doug Amorese, Dick Evans, Paul Wolber,Ar- lyce Guerry, Linda Lim, Ellen Deering, and Nalini Murdter for their aid and encouragement. I thank Donny Strosberg of Hybrigenics, Xu Li of Kaiser Per- manente, Steve Friend and Chris Roberts of Rosetta InPharmatics, Yiding Wang of Biotech Core, and Brian Ring of Stanford Univer- sity for images and figures. Thanks to Karen Guerrero of Mendel Biosciences for her encouragement and reviews and for educating me on some of the nuances of patent law. This book might not have been completed without the steadfast encouragement and expert guidance of Amy Murphy, McGraw-Hill’s pioneering “trade” science editor. I also thank Robert Cook-Deegan for his insightful comments. Finally, I offer my heartfelt thanks to Myriam Zech and Karolyn Zeng for their friendship and advice, Martin and Martha Zweig for their support, my daughter Marissa for her love and in- spiration, her mother Andrea Ramirez, and my mother Sheila Peckar. Introduction Institutions at the forefront of scientific research host a continual stream of distinguished guests. Scientists from throughout the world come to research centers, such as California’s Stanford Uni- versity, to share ideas and discoveries with their intellectual peers. It is part of an ongoing exchange that embodies the ideals of open- ness and cooperation characteristic of science in general, and bio- medical research in particular. As a graduate student in the Genetics Department of Stan- ford’s School of Medicine in the late 1980s, I attended several lec- tures per week by visiting scientists. We heard firsthand accounts of the latest triumphs of molecular biology, of newly discovered molecules, and of their roles in human disease. We heard of ele- gant, clever, and even heroic efforts to tease apart the molecular architecture of cells and dissect the pathways by which molecular actions lead to healthy physiology or sometimes to disease. And in our own research we did the same. If molecular biology ever had a heyday it was then. The intricate machinery of life was being dis- assembled one molecule at a time; we marveled at each newly discovered molecule like archaeologists pulling treasures from King Tutankhamen’s long-buried tomb. What’s more, a few of the molecular treasures were being formulated into life-prolonging medicines by the promising new biotechnology industry. Nevertheless, there was one guest lecture I attended during this heady time that left me cold. I had been told that Maynard Olson, a highly regarded geneticist then at Washington University in Saint Louis, had helped to develop a powerful new method for identifying genes associated with diseases and traits. But, instead of speaking about this technology or the genes he had discovered, Olson used our attention-filled hour to drone on about a scheme ix Copyright 2001 Gary Zweiger. Click Here for Terms of Use. x INTRODUCTION to determine the nucleotide sequence of enormous segments of DNA (deoxyribonucleic acid). The speech was a bore because it had to do with various laboratory devices, automation, and costs.
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