Cracking the Genome: Inside the Race to Unlock Human DNA

Overview

In 1953, James Watson and Francis Crick unveiled the double helix structure of DNA. The discovery was a profound moment in the history of science, but solving the structure of the genetic material did not reveal what the human genome sequence actually was, or what it says about who we are. Cracking the code of life would take another half a century.

In 2001, two rival teams of scientists shared the acclaim for sequencing the human genome. Kevin Davies, founding editor of Nature ...

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Cracking the Genome: Inside the Race To Unlock Human DNA

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Overview

In 1953, James Watson and Francis Crick unveiled the double helix structure of DNA. The discovery was a profound moment in the history of science, but solving the structure of the genetic material did not reveal what the human genome sequence actually was, or what it says about who we are. Cracking the code of life would take another half a century.

In 2001, two rival teams of scientists shared the acclaim for sequencing the human genome. Kevin Davies, founding editor of Nature Genetics, has relentlessly followed the story as it unfolded week by week since the dawn of the Human Genome Project in 1990. Here, in rich human and scientific detail, is the compelling story of one of the greatest scientific feats ever accomplished: the sequencing of the human genome.

In brilliant, accessible prose, Davies captures the drama of this momentous achievement, drawing on his own genetics expertise and on interviews with the key scientists. Davies details the fraught rivalry between the public consortium, chaperoned by Francis Collins, and Celera Genomics, directed by sequencer J. Craig Venter. And in this newly updated edition, Davies sheds light on the secrets of the sequence, highlighting the myriad ways in which genomics will impact human health for the generations to come.

Cracking the Genome is the definitive, balanced account of how the code that holds the answer to the origin of life, the evolution of humanity, and the future of medicine was finally broken.

Johns Hopkins University Press

...James Watson and Francis Crick discovered the double helix structureof DNA. The discovery was a profound, Nobel Prize-winning moment in the history of genetics, but it did not decipher the messages on the twisted, ladderlike strands within our cells...

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Editorial Reviews

From Barnes & Noble
The founding editor of the research journal Nature Genetics, Kevin Davies, presents the definitive account of the Human Genome Project -- both the publicly funded project led by Francis Collins and the private venture led by maverick Craig Venter.
Doody's Review Service
Reviewer: Ian Glass, MD, FRCP, FRACP, FACMG (University of Washington School of Medicine)
Description: This intriguing new book describes the climactic events underlying the human genome project and, specifically, the race to produce the first draft of the entire human genome sequence.
Purpose: The purpose of this engaging 300-page narrative is to inform the reader of the fascinating details behind the unfolding of this massive human achievement. By sketching in crucial steps and framing the pure science of this endeavor with a humanized account of the rivalries, big players (individuals and organizations alike), and the essential work of pioneering forerunners, the book is exceedingly comprehensive and big picture in its perspective and succeeds in a readable and enjoyable fashion. Although this is a single authored book, it spans a wide variety of sources and generally does a great job of fulfilling its aims of communicating the excitement and the potential of this epic achievement. The writing is concise and accessible, the book is deftly organized into 12 alluringly titled chapters, and, overall, it more than meets its aims.
Audience: A wide readership of scientists and physicians is anticipated, but this book should cross over to a more general audience. In fact, any student or professional desiring an in-depth discourse on the meaning and implications of the new genetics will greatly benefit from reading this book. Because minimal scientific background is required, this book has the potential to reach a wider audience and could be a very useful introductory text for a number of university courses from a wide variety of disciplines. The author is uniquely positioned and qualified to write such an authoritative account being at the epicenter of this endeavor in his role as the founding editor of Nature Genetics, where many of the most influential articles to emerge during the era were published.
Features: The book is plain but nonetheless accessible. The references/footnotes are well organized by page and the index is adequate. The uniqueness of this book lies in its enjoyable accessibility and its ability to fill in the gaps behind the human genome project as well as provide a plausible tangible overview.
Assessment: This outstanding narrative of this massive achievement communicates it superbly.
Sunday Times

For an up-to-the-minute account of one of the most dramatic periods in present-day science, Cracking the Genome is an essential read.

Los Angeles Times

A superb job... A tantalizing glimpse of the ethical perils and technological possibilities awaiting humanity.

American Scientist

A rollicking good tale about an enduring intellectual monument.

The Independent

The race is over, and Davies was there, all along, providing the running commentary—and there, too, at the finish line. In Cracking the Genome, he hands out the prizes.

Science News

Davies has tracked one of the most important stories ever to unfold. Davies helps readers understand how the deciphering of our genetic code will revolutionize our lives while posing serious ethical dilemmas.

Business Week

Investors and others looking for a quick primer on the science and business of biotechnology will find this a useful guide.

History and Philosophy of the Life Sciences
In Davies' prose, this story of molecular biology and the Human Genome Project is as compelling as any Arthurian legend. In a fast-moving approachable style, Davies captures the uncovering of biology's Holy Grail, relying on his own expertise in genetics and interviews with key players such as Collins and Venter.

— Margaret R. McLean

History and Philosophy of the Life Sciences - Margaret R. McLean

In Davies' prose, this story of molecular biology and the Human Genome Project is as compelling as any Arthurian legend. In a fast-moving approachable style, Davies captures the uncovering of biology's Holy Grail, relying on his own expertise in genetics and interviews with key players such as Collins and Venter.

Paul Raeburn
Investors and others looking for a quick primer on the science and business of biotechnology will find a useful guide in Kevin Davies Cracking the Genome
BusinessWeek
Publishers Weekly - Publisher's Weekly
The Human Genome Project, the effort to determine the full genetic composition of human beings, has consumed billions of dollars, involved thousands of scientists, captured the imaginations of millions of people and offered the promise of untold numbers of medical breakthroughs. Davies, founding editor of the journal Nature Genetics and author of Breakthrough: The Race to find the Breast Cancer Gene, does an impressive job of contextualizing the science within a political, economic and social framework, creating a lively tale as accessible to nonspecialists as it is to scientists. A quest for profits as well as accolades is shown to be an important force in shaping "what is, at the very least, an extraordinary technological achievement, and is at best perhaps the defining moment in the evolution of mankind." Most of the leading scientists involved, individuals such as James Watson, Nobel laureate and original director of the Human Genome Project; Francis Collins, Watson's successor; and J. Craig Venter, the entrepreneurial scientist who decided to compete with the publicly funded Human Genome Project using private money and untested computational methods, spoke openly with Davies about their hopes and desires. Davies does a fine job describing the basic molecular biology and genetics underlying the Project as well as many of the ways our newfound knowledge may be put to use, though he largely ignores the ethical considerations swirling around a lot of these options. Copyright 2000 Cahners Business Information.
Library Journal
From its inception, the Human Genome Project has been described in epic, aggrandized terms. The search has been likened to the quest for the Holy Grail; the genome has been called the "Book of Life," written in the "Language of God." Behind the hyperbole, though, is the work of mortal scientists who possess the entire gamut of human virtues and flaws. This is their story. The cast of characters includes James Watson, the co-discoverer of DNA structure; Craig Venter, a maverick, entrepreneurial geneticist; and many others. Along the way, egos clashed, principles were debated, and money, power, and prestige became major issues--but in the end, science prevailed. Davies (Breakthrough: The Race To Find the Breast Cancer Gene), editor of Nature Genetics magazine, has an insider's perspective on the entire story, which he tells at a rapid, engaging pace. The author notes that, as impressive as sequencing the genome was, interpreting and applying what we have learned is the bigger task ahead. Still, this is "halftime" for the Human Genome Project, and informed lay readers who want to follow the second half should read this book.--Gregg Sapp, Science Lib., SUNY at Albany Copyright 2001 Cahners Business Information.
Booknews
Drawing on his own genetics expertise and interviews with key scientists including Francis Collins, J. Craig Venter, Eric Lander, Kari Stef<'a>nsson, and John Sulston, the author (science writer and editor) describes the intense competition between public and private researchers to complete the process of mapping the human genome sequence. Annotation c. Book News, Inc., Portland, OR (booknews.com)

3 Stars from Doody
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Product Details

  • ISBN-13: 9780801871405
  • Publisher: Johns Hopkins University Press
  • Publication date: 10/1/2002
  • Edition description: New Edition
  • Pages: 352
  • Product dimensions: 6.00 (w) x 9.00 (h) x 0.91 (d)

Meet the Author

Kevin Davies is the founding editor of Nature Genetics and is currently editor-in-chief of Bio•IT World. He graduated from Oxford University and holds a Ph.D. in genetics from the University of London.

Johns Hopkins University Press

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Read an Excerpt

Introduction
We are digital archives of the African Pliocene, even of Devonian seas; walking repositories of wisdom out of the old days. You could spend a lifetime reading in this ancient library and die unsated by the wonder of it.

— Richard Dawkins

On April 1, 1993, two hundred guests gathered in a ballroom at an upscale Washington, D.C., hotel for an important birthday party. As the nervous host, I hoped everything would go smoothly: I had mailed invitations around the world, hung banners from the walls, and booked the best entertainment I could find. As the guests arrived, they paid compliments on how well the baby looked. How could I disagree? After a nerve-wracking twelve months as the sole editor of a fledgling science magazine called Nature Genetics, it was only natural to mark its first anniversary with a party.

Nature Genetics was a spinoff from the prestigious British journal Nature, which, since its inception in 1869, halfway through the reign of Queen Victoria, has been "nature's finest midwife, interpreter and namesake," in the words of Stephen Jay Gould. Another commentator called Nature "the chic place for scientists to disport themselves." Many of the science breakthroughs reported in the newspapers or on television every week are recapitulations of reports first published in Nature.

I joined Nature in 1990, leaving behind a less-than-auspicious career as a molecular geneticist, hunting for genes that cause terrible human diseases such as cystic fibrosis and muscular dystrophy. Determined to make an impression my first day at Nature's editorial headquarters, just off The Strand in London, I arrived dressed in an exquisite Italian double-breasted suit, only to discover a Dickensian office populated by a motley collection of disheveled journalists barely visible behind towering stacks of newspapers and magazines. The superficial air of civility could be shattered at any moment by an ugly fracas over the phone between an editor and the aggrieved author of a spurned manuscript. The editor, Sir John Maddox, was mostly sequestered in his office, protected by a staunch secretary and an impenetrable veil of cigarette smoke, although he would assuredly emerge late on a Monday to purchase a bottle of Bordeaux and two packets of cigarettes to help meet the weekly deadline.

As with any other magazine, Nature endured a few unfortunate incidents, notably the time that Maddox traveled to Paris in the company of his friend, the illusionist the Amazing Randi, to investigate the astounding claims of Jacques Benveniste that antibodies could leave a ghostly imprint in water. But despite such episodes, Nature's reputation remained secure. Among the thousands of reports that have graced its pages, including some of the most celebrated discoveries of the past century, one stands head and shoulders above the rest — indeed above the entire rest of the pantheon of scientific literature. In the spring of 1953, two precociously gifted scientists working in Cambridge, England, mailed a brief manuscript to the editor. As President Clinton told one of the authors almost fifty years later, the opening lines contained "one of the great understatements of all time." Then again, a certain sense of humility is in order when you have solved one of the mysteries of life. The letter began:


We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest.


Thus did James Watson and Francis Crick introduce the most celebrated scientific discovery of the twentieth century. The two-page letter contained just one drawing, a simple black-and-white figure for "purely diagrammatic" purposes. It was the first glimpse of the double helix, the defining scientific icon of the age, rivaled only by a sheep named Dolly.

Four decades after the discovery of the structure of DNA, human genetics research was enjoying a boom period. Researchers launched the first gene therapy trial, arranged the birth of the first genetically screened human embryo, and navigated their way across the twenty-three pairs of human chromosomes in search of genes that, when mutated, cause cancer and other diseases. A procession of exciting reports poured into the Nature office, and many worthy findings had to be turned down. On one occasion, Maddox questioned his biology editors for rejecting a paper reporting the mapping of the gene for an inherited form of Lou Gehrig's disease. "We must remember 'the David Niven factor,'" he said (the debonair British film actor had been another celebrity victim of motor neuron disease), because, after all, Nature was "in the business of selling magazines."

But the most important indication of the flourishing state of human genetics at the beginning of the 1990s was the start of an ambitious international program — the $3 billion Human Genome Project — to determine the complete instruction manual of humans by reading the precise sequence of the 3 billion chemical bases (A, C, G, and T) in human DNA. The smart editors at Nature, recognizing the significance of these developments, launched Nature Genetics in April 1992, with two noble goals in mind: first, to satisfy the prodigious output of human geneticists, and second, to sell more magazines.


The Washington first anniversary party was spread over two days, and the entertainment consisted of twenty of the most inspiring scientists that I knew of, ready to present the latest in cutting-edge research. As Maddox introduced the proceedings, I glanced at the program for reassurance. The meeting title, "Mapping the Future," was deliberately vague so that I could include speakers from all areas of genetics research. Of all those invited, only two people turned me down. Peter Goodfellow, the irrepressible chair of genetics at Cambridge University, would be missed, for he would typically dispense with slides altogether, drag a chair to the middle of the stage, and regale the audience with anecdotes. I was also sorry to lose the services of Bert Vogelstein, the brilliant Johns Hopkins University oncologist, but it was asking too much to postpone his son's bar mitzvah in Israel.

These absences notwithstanding, seated in the front rows of the audience was a veritable all-star cast. It included Berkeley geneticist Mary-Claire King talking about mapping the first breast cancer gene; an excited if exhausted Canadian, Marcy McDonald, representing the team that had just identified the mutation that causes Huntington's disease; Robin Lovell-Badge, the handsome heartthrob of my female production staff, who had identified the male "sex-determining gene"; Mark Hughes, who was helping to revolutionize genetic diagnosis; and the loquacious Ron Crystal, who would showcase the potential of gene therapy to treat diseases such as cystic fibrosis.

Just as baseball and football managers typically write in the name of their most indispensable player before all others when they pick their team, I had built the program around two figures with unrivaled drawing potential. The first was Francis Collins, a tall, lean figure from the University of Michigan, who had the distinction of publishing the first article in Nature Genetics — and for good reason. Collins had enjoyed a spectacular run of success since 1989. Working with a Canadian team, Collins identified the gene for cystic fibrosis, one of the most common genetic diseases among Europeans. Two years later, he isolated the gene for a cancer syndrome called neurofibromatosis (sometimes likened to the Elephant Man disease). He had also collaborated in the discovery of the Huntington's disease gene. Now he was hoping to go four for four by teaming up with King to snare the breast cancer gene — a glamorous, high-profile collaboration between two genetics superstars.

Collins's research record alone justified his prominent position in the program, as did his rare talent for public speaking. But there was one more reason, based entirely on rumors that had been swirling for the best part of a year. As Collins took the podium, he smiled and confirmed the worst-kept secret in town. He had agreed to accept an offer from NIH director Bernadine Healy to become the new chief of the Human Genome Project — the most ambitious, expensive, controversial project in the history of biology to sequence the complete human genetic code. (A formal press conference was held a few days later.) Collins would succeed James Watson, the founding director of the genome program, who had stepped down the previous year. For Collins, the opportunity to be entrusted with such a historic enterprise could not be passed up.

A successful conference needs to end on a high note, and the other name I had penciled into the agenda before anyone else was the closing speaker. J. Craig Venter had enjoyed an equally meteoric rise to the science stratosphere. While Collins was celebrating his discovery of the cystic fibrosis gene, Venter was toiling away at the NIH, a respected scientist but hardly a household name. That would change virtually overnight in the summer of 1991, when he described a revolutionary method for identifying the thousands of genes expressed in different tissues of the human body. Aided by one of the first commercially available DNA sequencing machines, Venter's laboratory found a way to produce reams of DNA sequence data on hundreds of genes simultaneously, when other labs could study only one gene at a time. His method effectively bypassed the 95 percent of the human genome that has no known function, widely dismissed as junk DNA, to zero in on the most important DNA sequences: the genes, which carry the instructions to make the thousands of proteins in the human body. Venter had inspired a revolution in gene sequencing that brought him great fame, wealth, and no small measure of controversy. He was now the president of a nonprofit DNA sequencing institute, bankrolled by a venture capitalist to the tune of $70 million.

By the end of the conference, Collins and Venter had left nobody in any doubt that they would play dominant — perhaps the dominant — roles in the quest to decipher the riches inscribed in the human genetic code. Collins was effectively the leader of an international army of researchers on a quest for biology's holy grail, in the process tracking down the flaws in our DNA that cause thousands of inherited diseases. Venter's powerful new approach to DNA sequencing and gene identification would lead to the rapid identification of the majority of human genes in a few years, and perhaps provide the ideal complement to the task of sequencing 3 billion letters of DNA on twenty-three pairs of chromosomes.

Venter was already happily ensconced in his new institute, a few miles away from NIH, when Collins moved his laboratory to Bethesda. (In fact, Collins was scheduled to move temporarily into Venter's old laboratory.) What nobody knew was that these two doyens of DNA were on a collision course.


Five years later, in May 1998, Venter dramatically changed the course of the Human Genome Project as he informed Collins of his plans to form a new company that would sequence the entire human genome years ahead of the established deadline of 2005. He would use a simple sequencing strategy he had perfected on the genomes of bacteria, hundreds of the most sophisticated DNA sequencing machines, and one of the largest civilian supercomputers in the world. The New York Times trumpeted the news of Venter's brazen attempt to claim what many considered to be the human birthright, and with it the unthinkable prospect that the public human genome project was on the verge of extinction.

The Wellcome Trust, a British medical charity, quickly reassured the genetics community by doubling its funding of the Sanger Centre, the premier British DNA sequencing institute. Its goal was to guarantee production of a definitive sequence of the human genome that would stand the test of time. Collins followed suit, boosting support for the most productive sequencing centers in the United States. By all appearances, the slow march to decode the sequence of the human genome had been transformed into an epic battle between two sides with vastly different strategies and agendas. Venter's intent was for his company, Celera Genomics, to sequence the human genome years before expectation (leaving thousands of gaps if need be), to be able to patent hundreds of genes and sell precious information about the genome sequence for a gene king's ransom to the pharmaceutical industry. Collins's task was to kick-start an unwieldy federal program to keep pace with Venter's private effort and deliver the complete, gold-standard sequence years earlier than projected, all the while releasing its DNA data every night to make the human genome unpatentable.

For two years, these teams traded insults and accusations in the press while feverishly racing to sequence the human genome. The stakes were enormous; prestige and priority were on the line. Collins and his allies doggedly insisted that they were not racing with Venter, but that the increased pace of sequencing was part of their original strategy. Venter convened press conferences to mark major milestones in the human genome sequence, and at a congressional hearing in April 2000, claimed he had finished sequencing the DNA of a human being. The public sparring threatened to sully what by rights should be one of the most dignified and welcomed accomplishments in human history. "Intense competitors sometimes trade a little trash talk, and the media love it," commented Donald Kennedy, editor-in-chief of Science magazine. "The emphasis on the race may have the effect of obscuring the real story here, which is a magnificent scientific achievement."

Suddenly, in June 2000, the "race" was declared over, and Collins and Venter agreed to bury their differences to restore a measure of dignity to the quest for the human genome. The hastily organized victory announcement was premature in many ways: Collins's consortium had not quite reached their stated target of a "rough draft" of 90 percent of the sequence, but had made all their data publicly available. By contrast, Venter said his sequence was 99 percent complete, but only a handful of subscribers to his database were in a position to verify that claim. However, these were mere technicalities. In a June 26 ceremony at the White House, Collins and Venter stood proudly beside President Clinton as he proclaimed, "Today, we are learning the language in which God created life."

Decoding the human genome is a staggering achievement, one that has been compared favorably to every major technological achievement, from the invention of the wheel to the landing on the moon. We are the first species with the intelligence to be able to read the text of life (and as one wag put it a few years back, stupid enough to pay for it). But just what does cracking the human genome mean? How can we put this achievement into its proper perspective?

"This is just halftime for genetics," said Eric Lander, the director of the flagship American genome center at the Whitehead Institute, shortly after the White House ceremony. "It started around 1900, and the really interesting second half of the game is about to begin." The game indeed began a hundred years ago, when three plant breeders discovered the forgotten work of Gregor Mendel, a Bohemian monk. Mendel had established the fundamental rules of play by demonstrating that the inheritance of traits (in Mendel's case, the color and shape of peas) was determined by pairs of factors, later termed genes, which could be dominant or recessive. Shortly after the rediscovery of Mendel's work, Sir Archibald Garrod proposed that a disease called alkaptonuria was caused by the inheritance of a recessive gene — the first human "inborn error of metabolism."

That genes were composed of DNA was all but established in 1944, but the discovery did not catch the popular imagination until the seminal discovery of Watson and Crick in 1953. Monochrome photographs show the two young scientists staring in awe at their model of the spiraling ladder of DNA. (The Apple computer company adapted a photo of Watson for its "Think Different" advertising campaign.) The helical structure provided the secret of DNA's passage from generation to generation, whereas the rungs of the ladder, made up of four simple letters, held the key to the code of life. As Crick and others deduced a decade later, the sequence of these bases literally spells out the instructions for the synthesis of the proteins in our bodies. The 1970s gave rise to the genetic engineering revolution, as scientists devised ways to manipulate and sequence DNA and began sampling human genes.

In the mid 1980s, a group of scientists began to formulate a plan to assemble the complete sequence of all 3 billion letters of human DNA. Harvard University's Walter Gilbert, who shared the Nobel Prize for DNA sequencing, hailed the challenge as nothing less than biology's quest for the holy grail. After years of argument about the cost and wisdom of systematically procuring the sequence, the Human Genome

Project finally got underway in 1990, with a scheduled completion date of 2005.

Early progress was rapid, highlighted by the identification of many genes that cause devastating diseases, including muscular dystrophy, Alzheimer's disease, and cancer. But the technology for painstakingly sequencing all 3 billion units of DNA moved more slowly. By the halfway mark of the project's 15-year mandate, only 3 percent of the human genome had been sequenced, raising doubts as to whether it would be finished on time. Venter seized this window of opportunity by coupling state-of-the-art DNA sequencing and computing technology with a daring DNA sequencing strategy. The test case was the genome of the fruit fly, one of the classic model organisms in biology, which Celera triumphantly completed in just four months in 1999. From that moment, there was little doubt that Venter would make good on his promise to sequence the human genome, years ahead of the original schedule.


Referring to the universe, Galileo wrote, "This book is written in mathematical language and its characters are triangles, circles and other geometrical figures, without whose help...one wanders in vain through a dark labyrinth." As we prepare for the second half of genetics, we know virtually the entire text of the human genome, a string of 3 billion letters — about 750 megabytes of digitized information — that would fill about 5,000 books like this, and yet fit onto a single DVD.

If the first half was eventful, the second half promises to be spectacular. In the next few years, scientists aided by powerful computer algorithms will sift through the human DNA lexicon to identify all of the human genes. How many they will find it is too early to say — estimates have ranged wildly from 40,000 to over 100,000. The immediate challenge is to learn what these genes do and to divine links between the millions of pinpoint variations in our DNA sequence and our susceptibility to countless diseases. These advances will enable doctors to screen an individual's genome to produce a personalized scorecard of risks for common diseases including heart disease, diabetes, and mental illness, as well as recommending the most effective treatments for these conditions.

Within a decade or two, we may be carrying this information on our own personal DNA DVD, replete with information on our genetic susceptibility to disease and our tolerance to drugs. Clinics increasingly will be able to select genetic traits in human embryos by screening DNA before implantation and employ novel gene-based therapies to replace or repair faulty genes to cure inborn illnesses and cancer. And by the end of the game, we may know even enough about the secrets of our own genome to associate genes with elements of human character. I haven't even mentioned xenotransplantation, stem cells, and cloning.

The human genome indubitably holds the key to our future, but perhaps even more significantly, it also carries the secrets of our past. Studies of the variations in the genome sequence between humans and primates will reveal our evolutionary journey over the past 5 million years. Genome studies also shed light on the movement of populations out of Africa and across the globe over the past 100,000 years, revealing hidden truths about our identity as a population and as a species. DNA sequence variations also provide a unique molecular fingerprint of the living and the dead. Such studies have added important chapters to American and Russian political history, and DNA fingerprinting is playing an indispensable role in the legal system.

What I hope this book offers is a view of genetics as we momentarily regroup at halftime. It is the story of the people who are responsible for what is, at the very least, an extraordinary technological achievement, and is at best perhaps the defining moment in the evolution of mankind. It looks back at the highlights of the first half and looks ahead to the rest of the game. This book is not intended to be the definitive record of the politics of the genome project, nor is it an anthropological exercise designed to reveal hidden truths about the process of science. Rather, my goal has been to capture the excitement, intrigue, mystery, and majesty of the quest for biology's holy grail.

It is impossible to predict the final result of the game with so much left to play for, but there can be no doubt that this treasure of genetic information will irrevocably change our view of our place in the world. Our children will be diagnosed for diseases they have not even developed and treated with drugs that match their body chemistry. Our grandchildren may be plucked from a pool of cells bathing in a petri dish after being screened for hidden flaws in their DNA. And our great-grandchildren will have dominion over the generations to come, with the capability to engineer traits into the genetic material as easily as sewing a button on a shirt.

If the double helix is the prevailing image of the twentieth century, just as the steam engine signified the nineteenth century, then the sequence — the vast expanse of 3 billion As, Cs, Gs, and Ts — is destined to define the century to come. DNA is essentially digital information, a 3-billion-year-old Fortran code. Now that we have cracked the genome, we face the ultimate challenge of understanding what the sequence means and what it can teach us. We have the awesome potential — should we so desire — of rewriting the language of God and the responsibility of harnessing the genome to improve the human condition in an equitable and ethical manner. The childhood of the human race is about to come to an end.

Halftime is over.

Copyright © 2001 by Kevin Davies

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Table of Contents

Introduction 1
1 Knights of the Double Helix: The Quest for Biology's Holy Grail 11
2 Reading the Book of Life: A Quick Voyage Around the Human Genome 33
3 The Eye of the TIGR: J. Craig Venter - Maverick Sequencer 52
4 Loading the Bases: Francis Collins and the DNA Detectives 69
5 The Circle of Life: Decoding the First Free-Living Creatures 94
6 Treasures of the Lost Worlds: The Keys to Human Disease from Tristan da Cunha to Iceland 119
7 Prize Fight: The Creation of Celera Genomics 141
8 The Story of Us: The Secrets of Who We Are 169
9 The Croesus Code: Passion, Personality, and Profit 192
10 The Eighth Day: Braving the New World of Designer Genes 216
11 The Language of God: A Defining Moment in the History of the Human Race 236
Notes 253
Acknowledgments 297
Index 299
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Introduction

On April 1, 1993, two hundred guests gathered in a ballroom at an upscale Washington, D.C., hotel for an important birthday party. As the nervous host, I hoped everything would go smoothly: I had mailed invitations around the world, hung banners from the walls, and booked the best entertainment I could find. As the guests arrived, they paid compliments on how well the baby looked. How could I disagree? After a nerve-wracking twelve months as the sole editor of a fledgling science magazine called Nature Genetics, it was only natural to mark its first anniversary with a party.

Nature Genetics was a spinoff from the prestigious British journal Nature, which, since its inception in 1869, halfway through the reign of Queen Victoria, has been "nature's finest midwife, interpreter and namesake," in the words of Stephen Jay Gould. Another commentator called Nature "the chic place for scientists to disport themselves." Many of the science breakthroughs reported in the newspapers or on television every week are recapitulations of reports first published in Nature.

I joined Nature in 1990, leaving behind a less-than-auspicious career as a molecular geneticist, hunting for genes that cause terrible human diseases such as cystic fibrosis and muscular dystrophy. Determined to make an impression my first day at Nature's editorial headquarters, just off The Strand in London, I arrived dressed in an exquisite Italian double-breasted suit, only to discover a Dickensian office populated by a motley collection of disheveled journalists barely visible behind towering stacks of newspapers and magazines. The superficialair of civility could be shattered at any moment by an ugly fracas over the phone between an editor and the aggrieved author of a spurned manuscript. The editor, Sir John Maddox, was mostly sequestered in his office, protected by a staunch secretary and an impenetrable veil of cigarette smoke, although he would assuredly emerge late on a Monday to purchase a bottle of Bordeaux and two packets of cigarettes to help meet the weekly deadline.

As with any other magazine, Nature endured a few unfortunate incidents, notably the time that Maddox traveled to Paris in the company of his friend, the illusionist the Amazing Randi, to investigate the astounding claims of Jacques Benveniste that antibodies could leave a ghostly imprint in water. But despite such episodes, Nature's reputation remained secure. Among the thousands of reports that have graced its pages, including some of the most celebrated discoveries of the past century, one stands head and shoulders above the rest -- indeed above the entire rest of the pantheon of scientific literature. In the spring of 1953, two precociously gifted scientists working in Cambridge, England, mailed a brief manuscript to the editor. As President Clinton told one of the authors almost fifty years later, the opening lines contained "one of the great understatements of all time." Then again, a certain sense of humility is in order when you have solved one of the mysteries of life. The letter began:


We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest.


Thus did James Watson and Francis Crick introduce the most celebrated scientific discovery of the twentieth century. The two-page letter contained just one drawing, a simple black-and-white figure for "purely diagrammatic" purposes. It was the first glimpse of the double helix, the defining scientific icon of the age, rivaled only by a sheep named Dolly.

Four decades after the discovery of the structure of DNA, human genetics research was enjoying a boom period. Researchers launched the first gene therapy trial, arranged the birth of the first genetically screened human embryo, and navigated their way across the twenty-three pairs of human chromosomes in search of genes that, when mutated, cause cancer and other diseases. A procession of exciting reports poured into the Nature office, and many worthy findings had to be turned down. On one occasion, Maddox questioned his biology editors for rejecting a paper reporting the mapping of the gene for an inherited form of Lou Gehrig's disease. "We must remember 'the David Niven factor,'" he said (the debonair British film actor had been another celebrity victim of motor neuron disease), because, after all, Nature was "in the business of selling magazines."

But the most important indication of the flourishing state of human genetics at the beginning of the 1990s was the start of an ambitious international program -- the $3 billion Human Genome Project -- to determine the complete instruction manual of humans by reading the precise sequence of the 3 billion chemical bases (A, C, G, and T) in human DNA. The smart editors at Nature, recognizing the significance of these developments, launched Nature Genetics in April 1992, with two noble goals in mind: first, to satisfy the prodigious output of human geneticists, and second, to sell more magazines.


The Washington first anniversary party was spread over two days, and the entertainment consisted of twenty of the most inspiring scientists that I knew of, ready to present the latest in cutting-edge research. As Maddox introduced the proceedings, I glanced at the program for reassurance. The meeting title, "Mapping the Future," was deliberately vague so that I could include speakers from all areas of genetics research. Of all those invited, only two people turned me down. Peter Goodfellow, the irrepressible chair of genetics at Cambridge University, would be missed, for he would typically dispense with slides altogether, drag a chair to the middle of the stage, and regale the audience with anecdotes. I was also sorry to lose the services of Bert Vogelstein, the brilliant Johns Hopkins University oncologist, but it was asking too much to postpone his son's bar mitzvah in Israel.

These absences notwithstanding, seated in the front rows of the audience was a veritable all-star cast. It included Berkeley geneticist Mary-Claire King talking about mapping the first breast cancer gene; an excited if exhausted Canadian, Marcy McDonald, representing the team that had just identified the mutation that causes Huntington's disease; Robin Lovell-Badge, the handsome heartthrob of my female production staff, who had identified the male "sex-determining gene"; Mark Hughes, who was helping to revolutionize genetic diagnosis; and the loquacious Ron Crystal, who would showcase the potential of gene therapy to treat diseases such as cystic fibrosis.

Just as baseball and football managers typically write in the name of their most indispensable player before all others when they pick their team, I had built the program around two figures with unrivaled drawing potential. The first was Francis Collins, a tall, lean figure from the University of Michigan, who had the distinction of publishing the first article in Nature Genetics -- and for good reason. Collins had enjoyed a spectacular run of success since 1989. Working with a Canadian team, Collins identified the gene for cystic fibrosis, one of the most common genetic diseases among Europeans. Two years later, he isolated the gene for a cancer syndrome called neurofibromatosis (sometimes likened to the Elephant Man disease). He had also collaborated in the discovery of the Huntington's disease gene. Now he was hoping to go four for four by teaming up with King to snare the breast cancer gene -- a glamorous, high-profile collaboration between two genetics superstars.

Collins's research record alone justified his prominent position in the program, as did his rare talent for public speaking. But there was one more reason, based entirely on rumors that had been swirling for the best part of a year. As Collins took the podium, he smiled and confirmed the worst-kept secret in town. He had agreed to accept an offer from NIH director Bernadine Healy to become the new chief of the Human Genome Project -- the most ambitious, expensive, controversial project in the history of biology to sequence the complete human genetic code. (A formal press conference was held a few days later.) Collins would succeed James Watson, the founding director of the genome program, who had stepped down the previous year. For Collins, the opportunity to be entrusted with such a historic enterprise could not be passed up.

A successful conference needs to end on a high note, and the other name I had penciled into the agenda before anyone else was the closing speaker. J. Craig Venter had enjoyed an equally meteoric rise to the science stratosphere. While Collins was celebrating his discovery of the cystic fibrosis gene, Venter was toiling away at the NIH, a respected scientist but hardly a household name. That would change virtually overnight in the summer of 1991, when he described a revolutionary method for identifying the thousands of genes expressed in different tissues of the human body. Aided by one of the first commercially available DNA sequencing machines, Venter's laboratory found a way to produce reams of DNA sequence data on hundreds of genes simultaneously, when other labs could study only one gene at a time. His method effectively bypassed the 95 percent of the human genome that has no known function, widely dismissed as junk DNA, to zero in on the most important DNA sequences: the genes, which carry the instructions to make the thousands of proteins in the human body. Venter had inspired a revolution in gene sequencing that brought him great fame, wealth, and no small measure of controversy. He was now the president of a nonprofit DNA sequencing institute, bankrolled by a venture capitalist to the tune of $70 million.

By the end of the conference, Collins and Venter had left nobody in any doubt that they would play dominant -- perhaps the dominant -- roles in the quest to decipher the riches inscribed in the human genetic code. Collins was effectively the leader of an international army of researchers on a quest for biology's holy grail, in the process tracking down the flaws in our DNA that cause thousands of inherited diseases. Venter's powerful new approach to DNA sequencing and gene identification would lead to the rapid identification of the majority of human genes in a few years, and perhaps provide the ideal complement to the task of sequencing 3 billion letters of DNA on twenty-three pairs of chromosomes.

Venter was already happily ensconced in his new institute, a few miles away from NIH, when Collins moved his laboratory to Bethesda. (In fact, Collins was scheduled to move temporarily into Venter's old laboratory.) What nobody knew was that these two doyens of DNA were on a collision course.


Five years later, in May 1998, Venter dramatically changed the course of the Human Genome Project as he informed Collins of his plans to form a new company that would sequence the entire human genome years ahead of the established deadline of 2005. He would use a simple sequencing strategy he had perfected on the genomes of bacteria, hundreds of the most sophisticated DNA sequencing machines, and one of the largest civilian supercomputers in the world. The New York Times trumpeted the news of Venter's brazen attempt to claim what many considered to be the human birthright, and with it the unthinkable prospect that the public human genome project was on the verge of extinction.

The Wellcome Trust, a British medical charity, quickly reassured the genetics community by doubling its funding of the Sanger Centre, the premier British DNA sequencing institute. Its goal was to guarantee production of a definitive sequence of the human genome that would stand the test of time. Collins followed suit, boosting support for the most productive sequencing centers in the United States. By all appearances, the slow march to decode the sequence of the human genome had been transformed into an epic battle between two sides with vastly different strategies and agendas. Venter's intent was for his company, Celera Genomics, to sequence the human genome years before expectation (leaving thousands of gaps if need be), to be able to patent hundreds of genes and sell precious information about the genome sequence for a gene king's ransom to the pharmaceutical industry. Collins's task was to kick-start an unwieldy federal program to keep pace with Venter's private effort and deliver the complete, gold-standard sequence years earlier than projected, all the while releasing its DNA data every night to make the human genome unpatentable.

For two years, these teams traded insults and accusations in the press while feverishly racing to sequence the human genome. The stakes were enormous; prestige and priority were on the line. Collins and his allies doggedly insisted that they were not racing with Venter, but that the increased pace of sequencing was part of their original strategy. Venter convened press conferences to mark major milestones in the human genome sequence, and at a congressional hearing in April 2000, claimed he had finished sequencing the DNA of a human being. The public sparring threatened to sully what by rights should be one of the most dignified and welcomed accomplishments in human history. "Intense competitors sometimes trade a little trash talk, and the media love it," commented Donald Kennedy, editor-in-chief of Science magazine. "The emphasis on the race may have the effect of obscuring the real story here, which is a magnificent scientific achievement."

Suddenly, in June 2000, the "race" was declared over, and Collins and Venter agreed to bury their differences to restore a measure of dignity to the quest for the human genome. The hastily organized victory announcement was premature in many ways: Collins's consortium had not quite reached their stated target of a "rough draft" of 90 percent of the sequence, but had made all their data publicly available. By contrast, Venter said his sequence was 99 percent complete, but only a handful of subscribers to his database were in a position to verify that claim. However, these were mere technicalities. In a June 26 ceremony at the White House, Collins and Venter stood proudly beside President Clinton as he proclaimed, "Today, we are learning the language in which God created life."

Decoding the human genome is a staggering achievement, one that has been compared favorably to every major technological achievement, from the invention of the wheel to the landing on the moon. We are the first species with the intelligence to be able to read the text of life (and as one wag put it a few years back, stupid enough to pay for it). But just what does cracking the human genome mean? How can we put this achievement into its proper perspective?

"This is just halftime for genetics," said Eric Lander, the director of the flagship American genome center at the Whitehead Institute, shortly after the White House ceremony. "It started around 1900, and the really interesting second half of the game is about to begin." The game indeed began a hundred years ago, when three plant breeders discovered the forgotten work of Gregor Mendel, a Bohemian monk. Mendel had established the fundamental rules of play by demonstrating that the inheritance of traits (in Mendel's case, the color and shape of peas) was determined by pairs of factors, later termed genes, which could be dominant or recessive. Shortly after the rediscovery of Mendel's work, Sir Archibald Garrod proposed that a disease called alkaptonuria was caused by the inheritance of a recessive gene -- the first human "inborn error of metabolism."

That genes were composed of DNA was all but established in 1944, but the discovery did not catch the popular imagination until the seminal discovery of Watson and Crick in 1953. Monochrome photographs show the two young scientists staring in awe at their model of the spiraling ladder of DNA. (The Apple computer company adapted a photo of Watson for its "Think Different" advertising campaign.) The helical structure provided the secret of DNA's passage from generation to generation, whereas the rungs of the ladder, made up of four simple letters, held the key to the code of life. As Crick and others deduced a decade later, the sequence of these bases literally spells out the instructions for the synthesis of the proteins in our bodies. The 1970s gave rise to the genetic engineering revolution, as scientists devised ways to manipulate and sequence DNA and began sampling human genes.

In the mid 1980s, a group of scientists began to formulate a plan to assemble the complete sequence of all 3 billion letters of human DNA. Harvard University's Walter Gilbert, who shared the Nobel Prize for DNA sequencing, hailed the challenge as nothing less than biology's quest for the holy grail. After years of argument about the cost and wisdom of systematically procuring the sequence, the Human Genome

Project finally got underway in 1990, with a scheduled completion date of 2005.

Early progress was rapid, highlighted by the identification of many genes that cause devastating diseases, including muscular dystrophy, Alzheimer's disease, and cancer. But the technology for painstakingly sequencing all 3 billion units of DNA moved more slowly. By the halfway mark of the project's 15-year mandate, only 3 percent of the human genome had been sequenced, raising doubts as to whether it would be finished on time. Venter seized this window of opportunity by coupling state-of-the-art DNA sequencing and computing technology with a daring DNA sequencing strategy. The test case was the genome of the fruit fly, one of the classic model organisms in biology, which Celera triumphantly completed in just four months in 1999. From that moment, there was little doubt that Venter would make good on his promise to sequence the human genome, years ahead of the original schedule.


Referring to the universe, Galileo wrote, "This book is written in mathematical language and its characters are triangles, circles and other geometrical figures, without whose help...one wanders in vain through a dark labyrinth." As we prepare for the second half of genetics, we know virtually the entire text of the human genome, a string of 3 billion letters -- about 750 megabytes of digitized information -- that would fill about 5,000 books like this, and yet fit onto a single DVD.

If the first half was eventful, the second half promises to be spectacular. In the next few years, scientists aided by powerful computer algorithms will sift through the human DNA lexicon to identify all of the human genes. How many they will find it is too early to say -- estimates have ranged wildly from 40,000 to over 100,000. The immediate challenge is to learn what these genes do and to divine links between the millions of pinpoint variations in our DNA sequence and our susceptibility to countless diseases. These advances will enable doctors to screen an individual's genome to produce a personalized scorecard of risks for common diseases including heart disease, diabetes, and mental illness, as well as recommending the most effective treatments for these conditions.

Within a decade or two, we may be carrying this information on our own personal DNA DVD, replete with information on our genetic susceptibility to disease and our tolerance to drugs. Clinics increasingly will be able to select genetic traits in human embryos by screening DNA before implantation and employ novel gene-based therapies to replace or repair faulty genes to cure inborn illnesses and cancer. And by the end of the game, we may know even enough about the secrets of our own genome to associate genes with elements of human character. I haven't even mentioned xenotransplantation, stem cells, and cloning.

The human genome indubitably holds the key to our future, but perhaps even more significantly, it also carries the secrets of our past. Studies of the variations in the genome sequence between humans and primates will reveal our evolutionary journey over the past 5 million years. Genome studies also shed light on the movement of populations out of Africa and across the globe over the past 100,000 years, revealing hidden truths about our identity as a population and as a species. DNA sequence variations also provide a unique molecular fingerprint of the living and the dead. Such studies have added important chapters to American and Russian political history, and DNA fingerprinting is playing an indispensable role in the legal system.

What I hope this book offers is a view of genetics as we momentarily regroup at halftime. It is the story of the people who are responsible for what is, at the very least, an extraordinary technological achievement, and is at best perhaps the defining moment in the evolution of mankind. It looks back at the highlights of the first half and looks ahead to the rest of the game. This book is not intended to be the definitive record of the politics of the genome project, nor is it an anthropological exercise designed to reveal hidden truths about the process of science. Rather, my goal has been to capture the excitement, intrigue, mystery, and majesty of the quest for biology's holy grail.

It is impossible to predict the final result of the game with so much left to play for, but there can be no doubt that this treasure of genetic information will irrevocably change our view of our place in the world. Our children will be diagnosed for diseases they have not even developed and treated with drugs that match their body chemistry. Our grandchildren may be plucked from a pool of cells bathing in a petri dish after being screened for hidden flaws in their DNA. And our great-grandchildren will have dominion over the generations to come, with the capability to engineer traits into the genetic material as easily as sewing a button on a shirt.

If the double helix is the prevailing image of the twentieth century, just as the steam engine signified the nineteenth century, then the sequence -- the vast expanse of 3 billion As, Cs, Gs, and Ts -- is destined to define the century to come. DNA is essentially digital information, a 3-billion-year-old Fortran code. Now that we have cracked the genome, we face the ultimate challenge of understanding what the sequence means and what it can teach us. We have the awesome potential -- should we so desire -- of rewriting the language of God and the responsibility of harnessing the genome to improve the human condition in an equitable and ethical manner. The childhood of the human race is about to come to an end.

Halftime is over.

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Interviews & Essays

Barnes & Noble.com Exclusive Author Essay by Kevin Davies

I got into science writing and editing in 1990 when I became a biology editor for the prestigious British science magazine Nature -- coincidentally the same year the Human Genome Project was launched. Two years later, I launched a monthly spin-off journal called Nature Genetics, devoted to the latest advances in human genetics. The first issue included articles written by Francis Collins, a pioneer in the search for major disease genes such as cystic fibrosis, and Craig Venter, who was almost single-handedly revolutionizing the sequencing of human genes. We knew they would be major figures in the years to come, but could not have anticipated what happened next.

There were several good books published soon after the Human Genome Project got off the ground, but that was ten years ago, and I didn't think the end of the project should go unmarked. When Craig Venter decided to launch a new company called Celera Genomics in 1998 that promised to finish the sequence years ahead of the public groups, I began thinking about writing a book that would chronicle one of the most stunning scientific achievements in history. Given my long-standing relationship with Venter, Collins, and other prominent scientists on both sides, I felt reasonably qualified to produce an accessible, objective account of the race to sequence the human genome.

But I also wanted to get beyond the personalities and focus on how this deluge of DNA information will impact our lives in the years ahead. (My working title in fact was The Sequence, which is how the book will be known in the U.K.) So I spend a lot of time in the book looking at the next wave of genetic diagnostic technologies, the impact of genetic analysis on the study of evolution and human origins, as well as other controversial issues such as gene patenting and genetic determinism.

The impact of DNA technology on medicine is astonishing. At one point in the book, I discuss an amazing technique called preimplantation genetic diagnosis (PGD), in which scientists can screen the DNA from a three-day-old embryo without harm, to find out whether it has inherited a potentially fatal genetic condition. Just a couple of weeks after I finished writing, there was a news story about the birth of a baby selected using PGD, who is not only healthy but also has a tissue type that could save the life of his older sister. It sounds like a scene from Gattaca, but it's already medical reality.

The public tends to get a very warped view of genetics in the media. One moment we're hearing about the miraculous discovery of a new cancer gene or disease cure, the next we're mourning a tragic death during a gene therapy trial or debating the safety of genetically modified food. People better get used to it, however, because in just a few weeks we will be celebrating the public release of the full 3 billion letters of human DNA -- the complete genetic heritage of humankind.

A venerable geneticist called James Crow says this is "halftime for genetics." I like that. The first half began in 1900 when Mendel's laws of heredity were rediscovered and is about to conclude with the publication of detailed reports from Celera and the public alliance on their analyses of the human genome sequence. The second half is just getting under way -- the quest to unravel the precise functions of the tens of thousands of proteins in every human cell, with all that will mean for discovering new, more effective therapies. If it's anything like the first half, we'll be in for a treat.

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Sort by: Showing all of 2 Customer Reviews
  • Anonymous

    Posted January 19, 2001

    fluffy but fun

    --a fun read that could use more real science as opposed to politics

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  • Anonymous

    Posted November 25, 2000

    An Important Accomplishment Behind, The Greater Challenges Ahead

    This book is a very important contribution to both the scientific and the business literature for the lay person. It provides an overview of the development of our understanding of heredity from Gregor Mendel¿s pioneering work until the human genome was 99 percent sequenced in early 2000. The book then looks beyond that remarkable success to outline the even greater and more challenging work ahead. By contrasting the expensive, slow public effort with the agile, rapid progress of private industry, the book is also a cautionary tale about how to accelerate scientific progress through private incentives. Many books about scientific advances focus a lot on the science. Cracking the Genome does that as well, but the book is improved by considering the personalities of the people involved, their interactions, public policy questions, ethical discussions, and science fiction like speculations about the eventual shape of the scientific applications of this work. These perspectives are valuable for expanding your understanding, as well as for making the book much more interesting. Frankly, the book could have used a little more science. I recommend that you read the recent book, Genome, as well which will give you a more detailed understanding of the underlying structure of the genome and how it works. The Human Genome Project was originally conceived of as a public project funded by three billion dollars in taxpayer money taking 15 years. At the half-way point in the project, only 4 percent of the human genome had been sequenced. A one-time NIH (National Institutes of Health) neuroscience researcher, J. Craig Ventor, had been arguing unsuccessfully for a computer-based ¿brute force¿ method as faster and cheaper. All of the M.D.s (who can be pardoned for not understanding the potential of math and computers) couldn¿t understand why it might work, and Ventor was vilified. He went off to found a private institute that made great progress using his methods. Then in 1998, he joined Perkin-Elmer. From there, he was able to complete the sequencing in 2 years using three hundred million dollars. So the work got done for about a tenth of the cost and about 8 times faster than the planned alternative. The public project was given vast increases in funds to try to keep up with Ventor¿s group, and both projects were completed within a few months. Victory was proclaimed at the White House, and both groups honored in June 2000. One of the most interesting parts of the book is that the controversy over patenting genes was started by NIH under Bernadine Healy. In the public press, this has been treated as an intellectual grab by private industry. In this light, it seems like a response to what the government did. I loved understanding the implications of having sequenced many different living organizations, and also the potential benefits from sequencing proteins and enzymes. Everything fell into place. I suspect that those who invest in biotechnology would especially benefit from this book. It looks to me like the large strides that we all hope for from this science may be further off than I had initially envisioned. Companies like Genentech were originally synthesizing normal human material, like human growth hormone. It is obviously a much tougher job to find all of the genes that may influence a disease (plus the environmental factors) and combine that understanding into a treatment. Then putting it through all of the testing can take another 8-10 years. I suspect that the big payoffs from this work are probably more than 30 years away. I hope not. Perhaps J. Craig Ventor and other stallbusting thinkers can conceive of useful short-cuts. I certainly hope so! After considering all of the fascinating issues in this book, I suggest you consider where else we might get better results from tinkering with incentives rather than by trying to use government as a vehicle to get the results. For e

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