Transducing The Genome: Information, Anarchy, and Revolution in the Biomedical Sciences

275 Pages·2001·2.1 MB·English

by  Gary Zweiger

transducing the
genome
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
abc
McGraw-Hill
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 [phone].
TERMSOFUSE
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-HILLAND ITS LICENSORS MAKE NO GUAR-
ANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACYOR COMPLETENESS OF
OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANYINFORMA-
TION THATCAN BE ACCESSED THROUGH THE WORK VIAHYPERLINK OR OTHERWISE,
AND EXPRESSLYDISCLAIM ANYWARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT
NOTLIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITYOR 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
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.
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
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.
He described technicians (or even graduate students) working on
what amounted to an assembly line. He analyzed the costs per
technician,as well as costs per base pair of DNA.It was as bad as
the rumors we had heard of factory-like sequencing operations in
Japan.It all seemed so inelegant,even mindless.
It was not as if DNA wasn’t inherently interesting.DNA was
(and still is) at the center of biology’s galaxy of molecules.Its se-
quence dictates the composition, and thus the function, of hun-
dreds of thousands of other molecules.However,in the past DNA
sequencing had almost always been directed at pieces of DNA
that had been implicated in particular biological functions, rele-
vant to specific scientific queries. What seemed so distasteful
about a DNA sequencing factory was that it would presumably
spew out huge amounts of DNA sequence data indiscriminately.
Its product would not be the long-sought answer to a pressing sci-
entific puzzle, but merely enormous strings of letters,As, Cs,Ts,
and Gs (the abbreviations for the four nucleotides that make up
DNA). Only a computer could manage the tremendous amount
of data that a DNA sequencing factory would produce.And com-
puters were not then of great interest to us.
In the late 1980s most biologists had little use for computers
other than to compare DNA sequences and communicate with
each other over a network that later evolved into the Internet.
Only a few of them embraced the new technology the way that
scientists in other disciplines had.Biologists were compelled by an
interest in organic systems, not electronic systems, and most rel-
ished the hands-on experience of the laboratory or the field.Most
biologists considered computers as being just another piece of lab-
oratory equipment, although some perceived them as a threat to
their culture.One day a graduate student I knew who had decided
to embark on research that was entirely computer-based found
himself in an elevator with the venerable Arthur Kornberg,a bio-
chemist who had won a Nobel prize for identifying and character-
izing the molecules that replicate DNA. Probably more than
INTRODUCTION xi
anyone else, Kornberg was responsible for establishing Stanford’s
world-renowned Biochemistry Department and for creating the
U.S. government’s peer-review system for distributing research
grants. He would later author a book entitled For the Love of En-
zymes. He was also a curmudgeon, and when the elevator doors
closed upon him and the unfortunate graduate student he report-
edly went into a finger-wagging tirade about how computation
would never be able to replace the experiments that this group did
in the laboratory.
Which brings us to the subject of this book.In the late 1980s
we were at the dawn of a major transformation within the bio-
medical sciences.I didn’t realize it at the time,but Olson’s lecture
and my colleague’s commitment to computation were portents of
exciting and significant things to come.The life sciences are now
undergoing a dramatic shift from single-gene studies to experi-
ments involving thousands of genes at a time, from small-scale
academic studies to industrial-scale ones,and from a molecular ap-
proach to life to one that is information-based and computer-
intensive. This transformation has already had a profound effect
on life sciences research.It is beginning to have a profound effect
on medicine and agriculture.In addition,it is likely to bring about
significant changes in our understanding of ourselves, of other
human beings,and of other living creatures.Change can be a rag-
ing bull, frightening in its power and unpredictability.The pages
that follow are an attempt to grasp the bull by its horns,to under-
stand the nature and origin of the “New Biology,” and to deliver
this beast to you,the readers.
Biology is being reborn as an information science,a progeny of
the Information Age.As information scientists,biologists concern
themselves with the messages that sustain life,such as the intricate
series of signals that tell a fertilized egg to develop into a full-
grown organism,or the orchestrated response the immune system
makes to an invading pathogen. Molecules convey information,
and it is their messages that are of paramount importance. Each
molecule interacts with a set of other molecules and each set
communicates with another set,such that all are interconnected.
Networks of molecules give rise to cells;networks of cells produce