Bold Science: Seven Scientists Who Are Changing Our World

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Bold Science: Seven Scientists Who Are Changing Our World Anton, Ted. 0716735121 9780716735120 9780585359946

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Bold Science Seven Scientists Who Are Changing Our World Ted Anton

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Text design by Cambraia (Magalhães) Fernandes Library of Congress Cataloging-in-Publication Data Anton, Ted. Bold science: seven scientists who are changing our world. p. cm. Includes index. ISBN 0-7167-3512-1 1. Science. 2. ScientistBiography. I. Title Q171.A614 2000 509.2'2dc21 [B] 99-059969 ©2000 by Ted Anton. All rights reserved. No part of this book may be reproduced by any mechanical, photographic, or electronic process, or in the form of a phonographic recording, nor may it be stored in a retrieval system, transmitted, or otherwise copied for public or private use, without written permission from the publisher. Printed in the United States of America First printing 2000 W. H. Freeman and Company 41 Madison Avenue, New York, NY 10010 Houndmills, Basingstoke RG21 6XS, England

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To the memory of Harry Anton, who taught me to be bold

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Science could explain people, but it could not understand them. E. M. Forster, Howard's End

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Contents Acknowledgments

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Introduction

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The Book of Life Craig Venter's Shotgun Genomics

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On the Road Susan Greenfield and the Magus

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Worlds in Profusion Geoff Marcy's Planetary Astronomy

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Dangerous Liaison Polly Matzinger's Evolutionary Immunology

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How Much Fun This Is Saul Perlmutter and the Supernova Cosmology Project

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The Art of the Woodpile Gretchen Daily and Nature's Services

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Drawn to Truth Carl Woese and the Archaean Revolution

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Conclusion Intimate Science, Big Questions

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Index

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Acknowledgments In writing this book I conducted more than one hundred and fifty interviews with researchers all over the world. I thank them all for taking time from their busy schedules to speak with me. Some who gave more than their share of time include, certainly, Craig Venter, Susan Greenfield, Geoff Marcy, Polly Matzinger, Saul Perlmutter, and Gretchen Daily. Without their patience and honesty, Bold Science could not have been written. Many other researchers generously gave of their time, and I acknowledge their critical assistance. I want to give special thanks to those who went out of their way to assist me, including Ralph Wolfe, Tony Kerlavage, Aravinda Chakravarti, David Smith, Carl Pennypacker, David Stahl, Gary Olsen, Ron Schwartz, Paul Butler, Steve Emmett, Ephraim Fuchs, Debra Fischer, Peter Atkins, Steve Maran, Susan Barns, Kevin Apps, Robert Kirshner, Paul Erhlich, and Alexei Filippenko. I want to acknowledge especially a group of research assistants, including Aimee LaBrie, Belinda Gordon, Stephanie Duschene, and the guiding insights of Eileen Murphy. The University Research Council at DePaul University provided a Summer Research Grant and two Competitive Research Grants during the course of my work. When I began my travels in Seattle, Kim and Patrick McRoberts generously provided a roof and good company. Without that assistance this book could not have been written. Several friends and colleagues read the manuscript in various stages of completion, including James Fairhall, Stan Cohn, Liam Heneghan, and Jonathan Gross. I thank my DePaul University students who read and commented on chapters.I benefitted enormously from their insight. Other readers who brought critical wisdom include Ann Finkbeiner, Rick McCourt, and Deborah Blum.

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In thanking all these people I hasten to add that any mistakes in this book, in its observations and conclusions, are distinctly my own. At W. H. Freeman and Company I thank especially Michelle Julet, whose excitement and wisdom helped guide this project, as well as wise and patient project editor Georgia Lee Hadler, designer Cambraia (Magalhães) Fernandes, production coordinator Julia De Rosa, and excellent copy editor Andrew Kudlacik. Thanks too to my agent Ellen Levine, who guided the business of making the book. A most special appreciation goes to my wife Maja, who once again bore with me in the travel, long hours, and rollercoaster of writing. This is a book about the loopy, fast action of thought. A researcher lingers after a lecture, runs into a stranger, or sticks to an idea beyond what anyone else thinks is worthwhile. No matter how many interviews an author conducts, retracing this creative process is a difficult proposition. Retelling the incidents that lead to a new insight, combining many minds working together in painful failures and childlike obsession, is a little like naming the unnameable. Recollections may vary. In relying on personal interviews to reconstruct some events or thought processes, I checked what I was told against the statements of other participants and published sources. In the case of one minor figure, I have indicated a name change to protect an individual's privacy. What follows is my attempt to capture the excitement of new ideas transforming our time. The best one hopes for is a fair representation, marked by metaphor and approximation, for a process that remains at its heart a mystery.

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Introduction It seemed an endless plane flight from Tokyo to Washington, D.C. It was 1990, before the time of air phones and laptop computers. For hours over the blackness of the Pacific, thirty-four-year-old researcher J. Craig Venter was alone with his thoughts. Memories from his Japan tour slowly wafted into his mind, He enjoyed giving talks on his conventional research into the biochemistry of the mind, but what had really captivated him and his Japanese audience was the infant study of genomics, the complete genetic program in the cell's nucleus. For years the Holy Grail of unlocking how DNA operated, how it shaped identity and life and death, had riveted the attention of science, But despite all the advances in the study of DNA, identifying even a single human gene took many years. The problem seemed staggering: humans had perhaps one hundred thousand genes, a fly had more than ten thousand. The solution of life's ultimate mysteries lay, it seemed, far in the future. Even though Venter was a successful researcher, with many articles to his credit, he was dissatisfied. As a young man growing up in California, where he struggled in school and preferred surfing and sailing, he had disliked science. He discovered his calling in an unlikely place, in Vietnam, where he learned at a field hospital and orphanage that life was unimaginably fragile and that no time should be wasted on anything less than central. Though he was bald now and to all appearances a typical government researcher, he still had the thick arms and drive of a competitive swimmer, one who felt angry about science's inertia. He peopled his lab with younger assistants who, like him, shared an obsession with attacking first principles and the biggest questions. Many of the Japanese scientists he met shared his speculative passion, and he enjoyed the give-and-take of discussion with them. The

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problem in genetics had to be solved by breaking through to the entire human genetic sequence, all at once, complete. To do that, he and others felt, one needed robots attached to computers, capable of analyzing thousands of DNA sequences at once. The trouble was that leaders in the field saw no chance of making this happen soon. If it was the solution, they said, it lay in the distant future with tremendous government spending. The abyss between knowing the rules of the game and actually playing it yawned like the night outside Venter's plane window. But something nagged at Venter. As he sat on the plane a part of his mind kept returning to the body's own mechanisms. The body knew how to find the right DNA automatically, and if he could tap into that, perhaps using very ordinary tools and connecting them in a new way, he could unlock the genetic code on a huge scale. It would transform the field by making the big picture visible. Then anything was possiblethe keys to heredity, disease, the shimmering structure and meaning of life. We live in a unique time in the practice of science. With the end of the Cold War's easy money and big-budget projects, many researchers began, out of necessity, using common technologies across disciplines. In this small, creative, complex-systems exploration, researchers found they could unlock the fundamental processes of life, thought, and the universe on a new scale. By combining the cheap tools of personal computers, remote sensors, the Internet, and basic artificial-intelligence systems, they began to open an exhilarating and frightening era in genetics, ecosystems, cosmology, and neuroscience. Many books have discussed this dawning century of scientific triumphof engineered life, accelerated intelligence, and new mastery of nature's complex systems. But no one has explained how this new millennium will happen. How do certain individuals at a certain moment in history lead their fields in a transformation of scale? This book profiles seven researchers of opportunistic science in key fields that are changing our world. Their scrappy creative approach results partly from a new fusion of unrelated fields, with professionals and amateurs collaborating around the world instantly, much as the Renaissance grew from Europe's discovery of travel, of Arabic, Oriental and classical knowledge, and from the breakdown of social hierarchy. In part, this new fluidity arises from the intense expansion of science media and interaction with the public. Most of these scientists are, in some measure, stars. They take advantage of the Web, newspapers,

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magazines, television, radio, and books to invite the public to join them on the edge of history. While past generations have produced beautiful theoriesof DNA's double helix, quantum theory, and the nature of the universe and our psychesthey were generally unable to apply these ideas. Darwin's theory of evolution gave us a dynamic model of life's history. Einstein's theory of relativity and the discovery of the expanding universe opened our perspective. The conception of these theories depended on simplifying evidence from the real world. The most fundamental problem remained: to master how such theories operate in a real universe of chance and accident, the world that science calls complex systems. We knew from Darwin that species evolve, for example, but how does this happen at the cellular or molecular level? Today we are unlocking such questions. What happened in the twentieth century, though, was the development of gigantic science, ever more specialized and bureaucratic, an approach that gave us triumphs like the atom bomb, high-energy physics, and moon landings. We began to think of all science as big science, when the truth was the most important discoveries have often been made by fairly small, sometimes amateur, even accidental projects. Since the time of Galileo science has usually been loopy, interdisciplinary, and humanistic as, well, any art form. And just as the telescope helped Galileo transform a vision of the cosmos to a larger scale, today the combination of computer, remote-sensing, and other technologies offers smaller, innovative teams the opportunity to transform our vision. Seeing and understanding the big picture of evolving organisms, climate systems, or star systems, has become for the first time a real possibility. A book telling the story of these seven research teams in such vastly different fields is itself a kind of experiment. Since I was a child I have always been fascinated by big questions, and by the minds that turned on them. Where does thought come from? How did the universe begin? How does knowledge advance? I loved books that showed a life of the mind in all its detective-thriller suspense. As I began pursuing the question of who was leading this creative science, I lurked at conferences like something of a spy, talking to experts, field leaders, and funding agencies, I learned that the ''three great themes in science in the twentieth centurythe atom, the computer, and the gene," to quote National Institutes of Health Director Harold Varmus, were combining to "revolutionize the twenty-first century," in the words of physicist Michio Kaku. But how, I wanted to know, and who? The names of

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creative researchers were not difficult to uncover. The same names, I found, cropped up time and again at conferences and in articles. I have chosen to focus on fields in the midst of change, on the verge, possibly, of a new way of understanding the world. These fields include genetics, with the imminent completion of the entire human genetic identity potentially "the single greatest scientific advance ever made," according to National Institutes of Health's Francis Collins. Craig Venter developed of many of the techniques driving the gene revolution. Neuroscience too is a field in the midst of chaotic change. The first woman ever to head England's venerable Royal Institution, Susan Greenfield, embodies in many ways the current controversies in the study of the mind. Ecosystems and astronomyour world and othersare also exploding into new scales of vision. The extra-solar planet-finder Geoffrey Marcy and the supernova explorer Saul Perlmutter have fundamentally altered our understanding of outer space. On our planet, the new link of economics and ecology led conservation biologist Gretchen Daily to explore a multidisciplinary view of nature. In health, many have written of a coming era of extended life through engineered body parts and new disease treatments, toward which immunologist Polly Matzinger is linking classical thought and cutting-edge medicine. Finally in biology, the discovery of new forms of life, perhaps vaster than all the life we knew until now, has caused an upheaval largely as a result of the pioneering work of evolutionist Carl Woese. This book proposes that the inner workings of discovery hold clues to the meaning of our time. In their mistakes and victories, cooperation and cheating, patience and ruthlessness, hype and insights, these people hint at a new moment in science, when small teams could think in a much bigger way than ever before. I found them remarkably open to discussing their thoughts on the question of coming fundamental shifts in science, If they had not been so willing, I could not have gone very far. I thank them for taking time from their packed schedules to talk with me. This book is written to uncover their habits of mind in the suspense of unfolding ideas. I choose seven representative stories, placing them side by side as a kind of comparative biography or narrative in a grand search for the keys to today's creativity. I picked these researchers because they demonstrate different methods and approaches to the architecture of change. Not all of them use computers, nor are all of them completely accepted in their fields. Many belong to newer or less known institutions, or come from private companies. Some are deeply controversial. A few are making

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fortunes. Portions of their work are questionable and contradictory, as some put themselves out on the edge of what science is or should be. They are significant because their research is helping to shape the policies and discoveries of our time. Picking them, however, I leave others out. Ultimately, this book's goal is not to provide a comprehensive view of the present, but to uncover the manners of thought shaping the future. Just as the last century saw a shift in economic power based on the machine-tool technologies of oil and electricity, today we are seeing a similar shift based on the synergy of the new machine tools of computers and biotechnology. These innovations in connections, of ways of orchestrating the world and seeing it whole, are changing what science can see. This change in what science can see amounts to a change in what scientists are. This collection explores how certain personalities came to the front of their fields at a pivotal moment. Thinking about them reveals, ultimately, the mystery of the human mind and the universe it apprehends.

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The Book of Life: Craig Venter's Shotgun Genomics 1 It was hot. The Quonset hut hospital smelled of dust, antiseptic, and diesel fuel. The sun glared. Helicopters raised an hourly din. Outside Danang, in Vietnam, Craig Venter evaluated the wounded as they were flown in. Twentyone years old, he decided who was to be saved and who was too far gone to waste precious resources on. Dodging rockets every night, he hated his job and yet was morbidly fascinated by it. A poor student who preferred surfing to his California high school, he stumbled into wartime triage by scoring highest of thirty thousand Navy service people on an intelligence test. He saw first-hand life's incredible caprice. One boy, for instance, died of a small bullet wound to the head. There was barely a nick. Venter helped with the autopsy, studying the boy's brain to see what had happened. The bullet had left barely a trace, he told a reporter later, with no other apparent damage. He was staggered that this would be enough to kill someone. Another time Venter saw a soldier, barely eighteen, with multiple wounds, who had lost most of his intestines. Doctors gave him a few hours. In the hospital, though, he lived for weeks, talking about how he wanted to get home and play basketball. How was it, Venter wondered, that one boy lived "without any guts, out of sheer determination" while another, with barely a nick, died? After he returned to his parents' home in suburban California, Venter kept asking himself big naive questions. Why did he live while

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all around him friends were dying? He signed up for community college in San Mateo with the idea of becoming a doctor in the Third World. He had seen villages bombed, children orphaned, and thousands of young men die. Gradually the idea of becoming a doctor came to be no longer enough. "What," he was asking himself, "is the mechanism of life in the first place?" Thirty-three years later Craig Venter was still asking those questions as he stood on the brink of making one of the single biggest contributions ever to understanding human identity. At a new biotechnology company called Celera, sitting in farmland a commuter train ride north of Washington, D.C., Venter was closing in on a first index ever of the three billion bits of information in the entire human genetic code. Cited as one of the three most influential scientists of our century by The Times of London, he was beating a $3 billion U.S. government joint effort with a consortium of university laboratories to open a new chapter in the history of biology. Most of us are aware of the genomics revolution, if not of the term. A gene is a single unit of life, a genome the entire set of genes in an organism. A short time ago, it took years to sequence, or analyze, a single human gene. But to be understood, genes cannot be studied individually. With one hundred thousand genes in a human, each with thousands of letters, genes operate together with other tissues, complex biochemical interactions, the environment, and chance, to make us what we are. To understand truly about disease, aging, identity, life, and death, one must know the whole genome. Obtaining that knowledge required multiple disciplines, automated techniques, creative financing, and a capacity to gamble. The headlines surrounding the human genome, however, hint at the deeper shift in thoughtfrom the reductionist to the inclusive, the cell to the whole organism, the gene to the genome. Like the eighteenth-century furor over surgery, the genomics revolution is an upheaval that extends far beyond science, complete with the passions, anger, violence, hyperbole, ethical conflicts, and financial bonanzas engendered by any sudden leap in human capability. "This is an exponential explosion," says Venter. "A hundred years from now we'll see this as a pivotal moment in human history." At the center of the maelstrom, Venter was sitting in a comfortable office with two of his standard poodlesCricket, asleep on the floor, and Shadow, edging me off his spot on the armchair by the fireplaceon the winter day I first visited him at his first research institute in 1997. Attached to his office was that of his wife, fellow geneticist Claire Fraser. He had decorated his walls with a framed astrology read-

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ing from the day he first published an organism's whole genetic imprint, a note from a Renaissance weekend with Bill and Hillary Clinton, and a model of his yacht, the Sorcerer. Driven and combative, he ran an informal lab. He let his assistants play rock and roll, loud. In the middle of a thought, he leapt to the window to point out a winter rainbow outside. He searched on the conference desk for a snapshot of a Caribbean double rainbow taken from the Sorcerer. He was rich. At the center of controversy, Venter was launching rockets while he transformed the practice of biology. That a researcher could become wealthy from the study of human genes was a hallmark of a new science of complex systems changing our lives and the way science happens. All this had been accomplished against almost impossible odds. After struggling in high school and serving his tour of duty in Vietnam, Venter "started his education from scratch," he recalled. "Things were not handed to me on a silver platter." He began as an obscure biologist who was turned down for an initial government grant in genetics. The most visible sign of the genomics revolution is Venter's race with the $3 billion joint government and university effort called the Human Genome Project, which plans to spell out the human genetic code by 2003. This, it could be said, is the traditional science approach. Venter planned to get it done by 2000. This, it could also be said, is one form of a new way of doing science. Why did this scientific quest become a race, and how did Craig Venter, an outsider to traditional science, become its leader? This revolution was made by linking tools. Venter's automated DNA sequencers and computer assembly programs together form an unlikely Renaissance magician's kit that promises to transform culture. They are already changing the way we live. To understand how, we must begin in an Austrian monastery. 2 Johann Gregor Mendel (1822 1884) was a monk fascinated by weather, sunspots, time travel, and plant hybrids. He bred pea plants to discover underlying patterns in life, as Enlightenment scientists had uncovered them in the heavens. Over many years in Brno, in Moravia, he grew thousands of short-stem and long-stem plants, then

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crossed them. He catalogued some twenty-eight thousand different results. From this chaos he intuited laws dictated by a living information carrier. In 1944 physicist Erwin Schrödinger followed with the book What Is Life? His book suggested that "genes," Mendel's information carriers, were not merely symbolic but physical entities that operate according to laws as discoverable as those of the new quantum physics Schrödinger helped pioneer. The book inspired Francis Crick, an English researcher taking too long to get his Ph.D., and a brash, frizzy-haired young American, James Watson. In Cambridge, they began seeking Schrödinger's and Mendel's "information carrier," not in proteins, where most contemporaries were looking, but in the acids, or DNA, of the cell nucleus. Crick and Watson built a model in their lab basement. Racing with the famous Linus Pauling in California, they were missing a key piece of information. Stymied, Watson was allowed to sneak a look at the London researcher Rosalind Franklin's slides from her x-ray crystallography (a technology that uses crystals as refractors of x-rays) of DNA. Franklin could not yet interpret her eerily beautiful "x" images, but Watson and Crick suspected exactly what they showed: DNA came in the form of a double helix. For that they won the Nobel Prize. About the time Watson and Crick were drinking glasses of champagne in Stockholm, Craig Venter was growing up in the San Francisco suburb of San Mateo. Born in 1946, he had two brothers and a sister. His father was an accountant, his mother a painter. Venter loved to surf, but struggled in high school because he could not remember facts, This hurt him in the rote education of the 1950s, making him suspicious of those who wielded facts like weapons. "I cannot visualize," he later told New York Times reporter Lisa Belkin. "When I close my eyes, I can't picture my wife. I can't picture my boat." After high school Venter headed for Newport Beach, where he worked at night to support his surfing during the day. He could sense the momentum of the water ten waves in advance, intuiting the best ones to ride. With the Army about to draft him in 1968, he enlisted in the Navy so he could compete on its swim team. While he was in training, however, President Lyndon Johnson announced the war's escalation and the end of military athletic teams. Venter took the service's IQ test, scored highest, he claimed, and signed up to be a hospital corpsman. Combat experience, along with work at a Vietnamese orphanage, drove him to a turning point. "I survived a year where a lot of people

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around me didn't. Seeing villages bombed, treating children, I saw the best and worst of medicine. I saw the deaths of thousands of people my age or younger," he says. "Coming out of there I felt I had to do something." Returning to California, he enrolled at a junior college. In a required composition course during his first term, Venter developed a friendship with his English teacher, Bruce Cameron. Cameron was new to teaching and felt he lacked insight into his well-to-do students, many of whom were experimenting with drugs. He noticed Venter though, who had taken to wearing Ben Franklin eyeglasses, for his "intelligence, wit, and insecurity due to his poor academic performance in high school." In the 1960s spirit, Cameron offered to let his students devise their own assignments if his were not "congenial to their style of learning." Venter was the only one to take up the offer, He wrote a series of stories about the failing health of a chainsmoking English teacher. The teacher was diagnosed with lung cancer. "Craig knew the grisliness of surgery," Cameron recalled, smiling, of his days as a teacher and smoker. "When the patient was on the operating table, he described what the lungs looked like, everything." The two became lifelong friends. Venter began stopping by to talk with Cameron about a book he was reading, The Double Helix by James Watson. In his coming-of-age story, Watson opened to the world the loopy and unlikely manner in which the DNA breakthrough happened. Years later Venter would complain that he had no mentors; what he did in science was too original. If there was one, he said, it was the Watson of The Double Helix. Combining brashness and brilliance, with a strong hint of self-promotion, the story foretold some of the controversies of Venter's own future. Watson and Crick had ended their short paper announcing their discovery in 1953 with the thought that DNA "suggests a possible copying mechanism" for genes. At the time Venter was reading the book, others around the world were feverishly building biochemical tools to explore how the "copying mechanism" works. Venter left San Mateo after a year. He headed for the University of California at San Diego, where he earned a B.A. in biochemistry and went on for a Ph.D. in physiology and pharmacology. What he did not know was that he would soon join the DNA race, and morehe would completely change its rules, bringing him head up against its hero.

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3 In graduate school Venter was told there were no questions left in biology; it would be hard to find a doctoral thesis worth writing about. He finished his B.A. and then a Ph.D. in a record short span of six years. Selected to join the lab of Nobel Prize-winning biochemist Nathan Kaplan, he studied heart cells and their adrenalin receptors "Those cells kept beating even if you put them all alone in a glass dish. They just never stopped. I had to figure out why." From Kaplan he learned how to think outside the assumptions in a field. Kaplan's lab connected him to the very beginning of the study of cellular biology. "Kaplan was trained by Fritz Albert Lipmann, who was trained by Otto Meyerhof, who invented the field," Venter recalled. But Kaplan was no longer as successful as he had been. "He had two hundred people working for him. He'd have a dozen good ideas a day, but the lab lacked the organization to act on them." From the beginning, Venter saw how wonderful ideas will falter under poor management. With his doctorate, Venter was offered a professorship and his own lab immediately at the State University of New York at Buffalo. This was an unusual leap; he skipped the usual postdoctoral tutelage under a "master." The leap made it easier to retain his creativity, he felt, to trust his intuition. Driven by some sense of being an outsider, by what he had experienced in his life, Venter worked at his heart cells, switching eventually to brain cells. The years passed in Buffalo. He applied for promotion and tenure and was approved. He published papers and gave talks. He sailed. He moved gradually from adrenalin receptors in the heart to the brain, as he became fascinated with the chemistry of thought itself. He took a second position as associate chief cancer research scientist in Roswell Park, Maryland, and applied for a position in neuroscience at the great national laboratory there. Before he left Buffalo, Venter met graduate student Claire Fraser. When she graduated with her doctorate, one of his competitors offered her a postdoctoral position. Venter asked her to marry him. "She agreed on the condition I never use that as a recruiting device again," he says. He landed a prestigious position as Section Chief in Neurology at the National Institutes of Health. At NIH, he became increasingly interested in the early rumblings of gene research. The code controlling adrenalin receptors of course had to lie in DNA. Young assistants

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gravitated to his intuition and supportive, challenging style, his "savvy for knowing the next big idea," says Tony Kerlavage, who joined him in 1985. Venter encouraged the good-natured Kerlavage to play with the new personal computers just being marketed by Apple. Then the first scientific paper came out announcing that a brain receptor gene had been sequenced, "We made a dramatic switch," recalled Kerlavage, "and set to learning molecular biology." The quest to read the sequence of DNA had long drawn the attention of the most adventurous and interdisciplinary minds. One pioneer was England's Fred Sanger, who made the first big step in molecular genetics ten years before Venter became interested. In 1977 Fred Sanger developed a technique in which DNA strands (which can run up to six feet long) could be snipped, amplified, and analyzed in a gel. Although he had won a Nobel Prize years earlier for his work with proteins, Sanger earned another for this early tool for linking genetics, molecular biology, and biochemistry. He made the first gene map of a simple virus, containing nine genes in all. But a virus is merely a snippet of DNA. Subsequent improvements brought ways of identifying genes in many microscopic forms of life, not just viruses, but it was still a painstaking, expensive, and Sysiphean task, taking many years and hundreds of thousands of dollars to isolate a single gene. The cell's genetic machinery was daunting, combining beauty and expediency. The double helix of DNA is a spiraling ladder of four different organic bases. Each of the thousands or millions of ladder rungs is made up of a pair of chemically linked bases. Long series of these "base pairs" make up a single gene. Series of genes in turn make up the forty-six chromosomes (twenty-three each from mother and father) in the nucleus of a human cell. The genes transfer their hereditary information to the rest of the body via messenger ribonucleic acid (mRNA), a worker molecule that transcribes as a copy of the sequence of bases in a gene; the mRNA then migrates to one of the cell's ribosomes, or protein factories, with its message. There the message is read to create the proteins that will make our characteristic bodies and mindsour blue or brown eyes, nasty or sweet temperaments, our penchants for opera or heavy metal, our capacity to dream or surf. The race was on to unlock the secrets of DNA. The people who began building the tools to pursue the Grail of gene sequences were business partners, rivals, and colleagues who often had moved over from other fields. They included the eccentric

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researcher Kary Mullis, at the University of California at San Diego, who manufactured his own hallucinogens and thought of his technique for reproducing genes in a test tube while driving with his girlfriend late at night, Mullis coined the term ''democratic science" for the small-team approach his technique made possible. Others began identifying genes for diseases, hereditary flaws, longevity. "I realized that this was where the real golden era was happening," recalled the leather-jacketed, motorcycling University of Michigan physician-by-training Francis Collins, who went on to identify the gene for cystic fibrosis and then, in 1993, to direct the government's Human Genome Research Institute. "I was completely blown away." 4 In deciding to pursue genes in the mid-1980s, Craig Venter faced several basic problems: first of all, his milliondollar lab was supposed to be studying neurology only, and second, isolating genes was still a slow, laborious human process that required a great deal of squinting to read enormous reams of data. Analyzing a single gene, one that produces a protein that serves as an adrenalin receptor in the brain, was taking him more than ten frustrating years. "I vowed never again," he says. The trouble was, life had very little to do with single genes. You can never say that Cain slew Abel because of a faulty gene. To understand behavior, you need to trace the complex biochemical pathways by which a gene might translate into a trait. To do that you needed the entire genetic sequence, the precise order of the rungs of the DNA ladder. It was the advantage of a top-priced topographical chart over a pocket world atlas for hiking through a dense uninhabited forest. You needed more than a map, you needed the sequence. "A genome 'map' just has crude landmarks, like towns," said Tony Kerlavage. "A 'sequence' has every address on every street of every city." DNA is powerful software. If one could ever fashion a DNA computer, it could pack a hundred trillion times the information stored in a current computer, according to physicist Michio Kaku. The task of separating the bits of such a potent code seemed impossible. Then

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Venter stumbled on a Nature article by Leroy Hood, who was at Caltech at the time. Hood had devised a way of attaching a different-colored fluorescent dye to each of the four DNA bases, with a laser beam to track them, a first step toward a machine that could decode genes rapidly and automatically. Venter took it upon himself to meet Hood, whose paper changed the landscape overnight. In 1987 Congress approved the first budget for the Human Genome Project, the seemingly quixotic quest to sequence all one hundred thousand human genes, under the directorship of none other than James D. Watson himself. That year, Venter got his lab named as NIH's test site for a prototype automated DNA sequencer. He connected with the high-tech firm Applied Biosystems and assigned lab assistant Jeannine Gocayne to make the prototype work. Venter sensed he had found a key in Hood's sequencer, one that Hood was not fully utilizing. Critics would accuse Venter of never doing original work himself. Hood for instance, envisioned the machine, and Gocayne became one of the best researchers pursuing automated analysis. But it was Venter who then put the two ideas together, parts into whole, theory into application. "I'm more the orchestra conductor," he said, but he was also envisioning the music. At NIH, Venter now gained support from James Watson himself. Watson saw in the DNA sequencer a way to harness the "copying mechanism" of life. But the path was difficult. Neither of them was overstating the humble machine's capability. The DNA sequencer was merely a tool. 5 Pursuing the sequence of thousands of genes, researchers faced two seemingly impassable roadblocks. The first was that only 5 30 percent of the human genome is ever expressed ("turned on") in a cell. These are the genes that do the actual work of lifegiving us our health or disease, adapting to changes in our environment. They make a liver cell a liver cell, a kidney a kidney, an ovary an ovary. The other 70 95 percent of hereditary material is therefore, it appears, attic trash left over perhaps from long extinct species. No one knows the purpose of the enormously long

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strings of dormant, or junk, DNA stashed in the chromosomes like old tourist key rings of the Sears Tower in a forgotten drawer. But the cell is a cosmic pack rat; it throws little away save for what is dangerous. We are, in short, walking museums. While this junk DNA offered tantalizing possibilitieslike being able to trace the history of evolution from primal cell to humanit makes gene indexing almost as formidable as combing a meadow for four-leaf clovers. To get to the expressed genes one had to waste months or years wading through an overwhelming amount of junk. By the time Venter left for a lecture trip to Japan in 1990, other researchers had suggested using the body's own devices to discard the so-called junk DNA. Several American and Japanese scientists talked about using RNA, the worker molecule, as a natural sifter of the wheat from the chaff. Messenger RNA transcribed only expressed genes, automatically ignoring the inactive. It was clonable, manipulable, and as industrious as the beating heart cells Venter had studied twenty years earlier. On his long plane flight home Venter thought and thought about the problem. For hours over the blackness of the Pacific, he let his mind wander. DNA is like a book. If the whole genome is the entire book, messenger RNA represents the abridged version, a Cliff's Notes of important passages. With the help of Sanger's techniques, he mused, one could turn the single-stranded RNA back into DNA, into a double-stranded synthetic molecule called complementary DNA (cDNA). Indeed, several labs were already searching cDNA collections, or "libraries," that had been created from mRNAs extracted from particular tissues or cultured cells. They were looking for specific genes that had already been related to some illness or trait, spending months and months sifting and analyzing. The trouble was, that each time you went looking for a gene, you had to sift through the same libraries again and again. Why not sequence all the different cDNA molecules at once, organizing them into one master index? You could build a library that a future researcher need simply consult, rather than search everything again and again. This idea, making use of shotgun cDNA cloning (so named because the cloned colonies looked like grapeshot), had the potential to be a "totally new discovery process," said Tony Kerlavage. "It's not driven by looking for a single thing, but by asking, well, what's here? Let the organism tell you," It was a eureka moment. Venter could barely contain himself waiting for the plane to land at Dulles.

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But when he got to his NIH lab at Bethesda, almost everyone told him he was wrong. Another team had tried the shotgun approach in muscle tissue. They had found only a few genes for proteinsactin and myosin. All he would end up with, they said, would be the same old same old genes for routine tissue. One person who listened, though, was a young beginning postdoc from North Carolina, Mark Adams. They held one ace; because Venter was in neurology they were searching in brain tissue, not muscle. Venter assigned Adams to partly sequence brain cDNA from available libraries and analyze the results with their new computer program. Almost immediately they began coming up with new genes. Brains, it turned out, contained a glut of new genes. They switched to the testis. It too, perhaps not surprisingly, was rich in new genes. They were discovering hundreds. Excited, Adams and Venter met with Kerlavage to name their revolutionary technique. Suddenly, it seemed, the whole genome was in reach. One could complete in weeks what took other researchers whole lifetimes. Kerlavage suggested the term "expressed sequence tags" for the short sequences of bases that they were using to uniquely index the cDNA molecules without reading their entire sequences. The name stuck. The idea of expressed sequence tags (ESTs) marked the first breakthrough, but a second advance a few years later was even more important in Venter's minddevising the computer program to reassemble the pieces of information they generated. The EST libraries were the genetic equivalent of scissoring up the Sunday New York Times into hundreds of thousands of tiny fragments. The challenge of reassembling them properly meant devising a program that would look for partial sequences that were repeated in different cDNAs, which implied that they overlapped. It was a gargantuan task. The genomics revolution was about to be launched. Soon they would be on the leading edge of a new complexsystems science they had simply been observing and critiquing. They now saw the capability of seeing the world whole, and eventually of manipulating it. The revolution came not from expensive technologies, but rather from creative connections among existing toolsautomated analysis, personal computer, and, eventually, the Internet. But a professional crisis had to happen first.

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6 The more success Venter had, the more his star rose. He was appointed to head a multidisciplinary team to explore the uses of the shotgun method. Convinced he had the technology in his lab to nail a good portion of the human genome, he applied for some $10 million for EST research. He was turned down, he was told, mainly because he was asking for a huge chunk of what was then a humble Human Genome Project budget. Venter felt, however, that Watson had undercut him. Venter's speedier approach, he suspected, might cause Congress to question the much larger amount of money it was spending on the more conventional slower method of sequencing. Venter continued, locating by June 1991 some 347 human genes and, within a year, 2,375 more. By the end of 1992 he had found another 4,448. The rest of the world had only uncovered about 2,000. As he achieved greater mastery, however, his relations with other researchers cooled. Venter's shotgun technique was obvious, they said; it was simply a new relationship, not a new discovery. "He got lucky," complained one researcher. "Anyone could've done it." Other criticisms were not so muted. Such objections would be a common theme for almost every one of Venter's innovations; others had seen it, but he was the first to make it work. Meanwhile, he was identifying twenty-five new genes every day. In 1991, under the urging of the NIH Technology Transfer Director Reid Adler, the NIH sought to patent hundreds of the ESTs Venter had located. The irony of what followed was that Venter never applied for the patent for himself; in fact, he and Mark Adams opposed the idea at first. "NIH sought the patent. But everyone was out to get me." Venter said. "It was a very difficult time." Patents of new techniques in government-funded research are common, indeed critical for the free flow of ideas (why tell others about your technique if you do not get the credit for it?). Insulin is commercially available today because the technique for isolating the human gene that encodes it was licensed and used to implant the gene in pigs. The furor over patenting of genes like insulin, though, had been building. Critics asked: How could you patent a human gene? How could it belong to someone? The response is that patenters invest in developing sophisticated techniques that isolate, artificially extract, or enhance the gene. Expressed sequence tags, the NIH argued, were a technique that enabled researchers to generate and use genetic information.

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The patenting of ESTs, though, made researchers even angrier. ESTs were not whole genes, just snippets. How could you patent a snippet of something whose uses you did not yet know? Researchers exploded, "The idea of having to buy information that so many of us need, its not science," said one. In cover stories from The Wall Street Journal to The New York Times, their anger focused on Venter. By now his combative reputation amongst them exceeded his own combativeness, which was considerable. Years later, in fact, the American Association of Inventors was considering him for its annual award for innovation. They could not believe it when he told them he did not have a single patent to his name. The worst part was that the NIH's James Watson, famous with reporters for his cutting wit, led the assault. Watson called the idea of EST patents "sheer lunacy." Watson's assistant claimed, "any monkey could do it!" Days later, The New York Times reported, a scientist in Venter's lab came to work dressed in a monkey suit. Friends took a photograph of him reading a book by Watson. The upheaval transformed careers. Responding to the general problem of ethics in patenting genes, James Watson decided to devote a significant percentage of the Human Genome Project budget to a study of morals, inviting science critics to participate. Shortly thereafter, he left the Human Genome Project altogether, returning to his post as Director of the innovative Cold Spring Harbor Laboratory. Turned down by NIH, Venter was pursuing ESTs on his own. But still, he felt like a target. The assault got so bad he contemplated leaving science completely. Others had glimpsed the future, however, and saw the money it could generate. A Wall Street venture capitalist, Wallace Steinberg, had been following Venter's work and understood its enormous implications. With the new leap in capability, one could search efficiently for genes to cure cancer, resist AIDS, delay the aging process, or select for intelligence and athletic prowess. Researchers could seek unknown genes in isolated populationsNew Guinea tribes, Amish familiesthat offered unimagined qualities of health and resistance, qualities potentially worth a fortune. While Venter had often received business offers, Steinberg had something completely different in mind, in scope and independence. In 1990 he called to offer a onetime-only deal: $70 million of his clients' money and Venter's own institute. All Venter had to do was enter into an agreement with a former Nobel nominee, William Haseltine. Venter would do the research science, and Haseltine's company, Human Genome Sciences (HGS),

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would figure out the profitable applications. Wallace Steinberg would handle the selling. At the time, Venter and Claire Fraser sat and talked it over. The stakes were enormous. But the possibilities dwarfed what you could imagine. "The complete genome revolution has not yet begun. We're still in the early phases of it," said Venter, The revolution was scientific, of course, but it also signaled a tidal shift in the management of science and of the vast fortunes that would soon be pouring into even obscure molecular biology research. Venter signed on with Steinberg and Human Genome Sciences, Genetic research would never be the same. 7 Venter founded The Institute for Genomic Research (TIGR) in an abandoned industrial park on July 6, 1992. He eventually moved to a sleek building a few miles down the road, where he installed the brass tiger outside the upperstory office he shared with Claire Fraser. At TIGR Venter challenged computer scientist Granger Sutton to devise software to reassemble the bits and pieces of cDNA by patterns of recognition. They dubbed the program the TIGR Assembler. Combined with the EST method, it offered the possibility of seeing the big picture, the whole genome of an organism. Venter did not want to sever his ties to academic science. In 1993 he met Hamilton Smith of Johns Hopkins University, who had won a Nobel Prize for his work on restriction enzymes, at a bioethics meeting in Spain. Smith was sitting in the hotel bar when Venter introduced himself. "I knew him by reputation," the avuncular Smith recalled, "which wasn't very good at the time." As they began talking about how they had gotten into science, though, they realized they both had been changed by their time in the military. Smith had worked at a naval dispensary and hospital during the Second World War. Their talk continued over dinner. "We hit it off so well, Craig asked if I wanted to be on the advisory council for TIGR," Smith recalled. At their first board meeting Smith suggested that they sequence the entire genome of Haemophilus influenzae, a bacterium that

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causes a number of ailments, including ear infections and even meningitis. Smith was an expert on Haemophilus. No one had sequenced a whole genome before; it would be a tremendous leap if they could do it. Understanding this one might mean new medical treatments. "But we took it strictly as a test case for the shotgun method," said Smith. Smith encouraged Venter to apply for money from the NIH. "Given his reputation, it was strictly in their face," he recalled, laughing." "E. coli was taking them ten years, and costing $10 to $12 million dollars." TIGR said that they could do their bacterium, with its two million base pairs, for half a million. Waiting for word on their application, they began working on their own, "Craig doesn't accept 'it can't be done' as an answer," said Mark Adams. That independence was vital, because in January 1994, the NIH turned them down. The rejection letter noted that "to date there is no successful example assembling two megabases of finished sequence and no indication that this can be achieved by the TIGR group." Venter framed the letter and used it to drive his staff. The small team stayed up late at night working to complete the first free-standing organism's whole genome. They were already nearly 90 percent done. When they emerged in May, Venter announced the feat at a microbiology conference: the first complete script of a living organism ever; with Hamilton Smith, they displayed the full color-coded map of the H. influenzae genome. The accomplishment was so revolutionary that Science put Haemophilus influenzae on its cover. Later TIGR published in Nature its colorful sequence of thirty-five thousand human genes. The imagery was fascinating: the genomes looked like cubist colored wheels with radiating spokes of tags and numbers. They were soon joined by more genome sequences, including those of the pathogens that cause syphilis and Lyme disease. TIGR's published papers became for a time the most quoted in all of science. The images seemed to suggest infinitely rich possibilities in their comparison, The human genome looked remarkably similar to that of most every other living creature, past and presentmice and worms, bacteria and algae, mastodons and jellyfish. Our different races have virtually the same genome. Aborigines and Eskimos, Kikuyu and Caucasians, Muslims and Jewswe have far less diversity than, say, fruit flies. The evolutionary messages were profound. The more he looked at the pictures, however, framed like art in the entrance hall of TIGR, the more Venter felt impatient and frustrated. It became apparent that genome sequences themselves would offer no

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intuitive breakthrough. "I looked at this thing we had tried so hard to get," Venter said, "and I expected to see some magical answer there." The grumbling about the lucrative finances of his research institute increased. Venter was growing dissatisfied with the manner in which Human Genome Sciences delayed findings to see if there were profitable applications. The original agreement had been that HGS would delay only a small percentage of data, and only by six months. "I found out," Venter told Discover's James Shreeve, "they lied." Haseltine responded that no delays in publishing data were ever invoked. Whatever the truth was, the relationship between the men was deteriorating. Wanting once and for all to separate himself from the charges of opportunism, and also ready to cash out, in the spring of 1995 Venter sold his 10 percent share of HGS stock for $9 million. It seemed a staggering gain, but when the stock tripled over the following five years it showed, Venter maintained, that his interest was always in the science, not the money. The controversies, however, were just beginning. TIGR had launched a spectacular trend. Soon other pharmaceutical companies ("big pharma") were gambling huge sums on research into genetic treatments for obesity, disease, and psychological disorders. "Venter's paradigm shift wasn't scientific," said Maynard Olson, "It was managerial.'' Overnight, biochemistry conferences shifted from sleepy gatherings to high-stakes conclaves of scientists, patent attorneys, investors, and hustlers. In back hallways paper-givers in rumpled suits pitched new techniques. With growing investment came a new culture of secrecy. "There's a fear that labs aren't publishing," Stanford researcher David Cox told Science. "It could become a nightmare." In Salt Lake City in 1994, for instance, Myriad Genetics, Eli Lilly, and the Lilly subsidiary Hybritech paid $14 million for commercial rights to develop the discovery of the BRCA1 gene, linked to breast cancer. In 1995 in California, the biotechnology firm Amgen paid $20 million for the exclusive right to develop a gene thought to regulate obesity. In 1997 Roche signed a deal to develop a small company's gene and the associated protein linked to inflammation. Today, not only insulin but many drugs are available because of patented human genes. "There was a huge shift. Where once the pharmaceutical companies were five to ten years behind the scientific community," Venter said, "now they're five to ten years ahead." Defenders of the trend pointed to the last century, when formidable scientists like Thomas Edison (who cofounded the preeminent journal Science as a way of speeding both information and investment)

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and George Westinghouse turned their prowess into control over new corporations like General Electric and Westinghouse. The risks new investigators take are enormous, and financial support would be impossible without the hope of a payoff. Detractors, however, noted that Edison and Westinghouse waited until their products were marketed to earn their money. There was a limit even at TIGR. Arguments broke out every time Venter sought to publish a new finding and Haseltine told him to wait to see if there was a commercial application. Still, there was a lighter side. When Venter published an obscure research article suggesting that humans probably had only sixty thousand genes, fewer than the one hundred thousand often cited in the science literature, he received an angry telephone call. "What do you mean sixty thousand?" Wallace Steinberg's voice screamed over the receiver. "I just sold Smith Kline Beecham a hundred thousand!" What Venter wanted most of all was to pursue the big questions. In June 1996 with its third organism sequence, for instance, TIGR entered into a profound controversy in fundamental biology. They published a sequence of a strange organism called Methanococcus jannaschii, which survived in thermal vents around volcanoes deep in the ocean. The organism was vitally important because it represented a new form of life, theorized by University of Illinois researcher Carl Woese, called archaea, the kind of life form astronomers thought would survive on other planets and moons. But more important, archaea illustrated Woese's controversial theory about the evolution of life, which could alter the structure of biology itself. Woese's idea was attacked, but sequencing the genome helped prove his point. The fact fact that 56 percent of the Methanococcus genes were completely unknown to biology hinted at "how little we know about life," said University of California molecular biologist David Smith. The world became a far more mysterious place. For pure science research, the genomics challenge became to marry Mendel's classical genetics with the new molecular genomics, theory with application. In 1996 at a Renaissance weekend with the Clintons, Venter talked of the incredible potential of genomics for the most basic science of biology. "You could track the entire history of life on Earth, theoretically, by looking at all the nonexpressed genes." The journey had come full circle from its beginning in an Austrian monastery a century and a half ago. As his business experience with Human Genome Sciences grew more and more uncomfortable, Venter watched as other researchers

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took off after fundamental biology. Researchers began trying to harness many of the complex functions of the body's mechanismsits antibody production, cell signaling, techniques of rejuvenation and repair. The applications touch fields from germ warfare to extraterrestrial life, from cystic fibrosis to depression. But no single thinker, it seemed, had triggered one leap as Watson and Crick had. "Genomics is rather more like the interstate highway system," said Maynard Olson. "Using existing technologies, a system was created that changed the culture." Finally, for Venter, the relation with HGS became beyond repair. Wallace Steinberg died in 1995, and in 1997 TIGR split with HGS. In so doing, Venter claimed he lost $38 million in future profits. The next day TIGR published all its genomic data on its website. 8 Venter of course was not the only player in the genomics revolution. As with the computer industry, the first phase of genomics was the entrepreneurial tool-making phase, and small, creative, and interdisciplinary labs like Venter's drove it. When a General Electric researcher visited Maynard Olson's early laboratory in St. Louis, for instance, he was shocked. Twenty times more money and manpower, he said, went into a new refrigerator model than into the early work on genomes. "There were no published tables," Olson said, of the reluctance of engineers to help him design his machines. "No specifications. We had to invent it as we went." Researchers sold their art as goal-driven and cheaper than much of the big-ticket research of the Cold War. They resembled impresarios of the gilded agemen like Edison and Insull, who built the infrastructure of the electric age and also enriched themselves. When the first wires were strung, no one could envision the computers they would power. Maynard Olson looked a little like comedian Dana Carvey's character Garth, and he functioned as all around gadfly in the field of hype. He punctured pie-in-the-sky claims about exotic technologies. Ironically, the biggest naysayers of the genomics revolution were the traditional geneticists. "The idea is not to get lost," Olson reminded a San Francisco audience of microbiologists in 1997. "You have to make this an interdisciplinary science."

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That the revolution occurred in such a short span of time with initially slack funding was remarkable. It was driven not by technology, but by people making new connections. The people pursuing gene sequences picked on the nascent technologies to connect biology and information science. By the early 1990s, for instance, Stephen Fodor, a Santa Clara, California, programmer bored with chemistry, formed the biotechnology company Affymetrix and began trying to link superconductors and DNA in DNA chips. The Affymetrix GeneChip may change the way we attack disease by allowing scientists to create enormously complex models that track mutations. Yet within a few years, younger researchers were creating less expensive do-it-yourself microarrays in much the same way that the Linux free software challenged Microsoft Windows. The Internet became the medium of choice for the publication of hugely complex genomes. ("We can't publish genomes on paper any more," says Tony Kerlavage. "They're too long.") You can find parts of the human genome at the website for the National Human Genome Research Institute. Funding agencies, seeing the results of work by people like Venter and Fodor, began actively promoting genomics' multidisciplinary systems approach. At the end of 1997 Vice President Al Gore held up the nickel-size Affymetrix device at a White House briefing, declaring it medicine's "most exciting new tool.'' The new paradigm of life became information. "Biology is no longer a life science, but an information science," announced Leroy Hood, by then at the University of Washington, in 1997. It seemed by then that Venter was entering a mature phase of yacht racing and public speaking, much like James Watson himself. Then came Celera. By early 1998 TIGR was pursuing all sorts of possibilities. In the spring, with air strikes again pounding Iraq, Venter and a pair of other researchers met with President Clinton and the cabinet to discuss genomic approaches to defense against biowarfare. We could build battlefield DNA sequencers, Venter promised. We could find the organism and know exactly what it was in a matter of seconds, giving us the key to combatting it. Much as Galileo sold his telescope to governments as a military tool and to philanthropists as a tool of art, so too Venter proved a good showman as he returned to his battlefield inspiration for science. He had his eye on old friend who was coming out with a new, incredibly efficient DNA sequencer. Mike Hunkapiller and Venter had been rivals in the late 1980s, in the days of the first sequencer.

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Hunkapiller had been a postdoc with Leroy Hood, the one who actually developed Hood's laboratory model into a working sequencer. Now a vice president of Perkin Elmer, he was bringing out a new model sequencer, the API 3700, orders of magnitude faster than the 370s Venter used. By the spring of 1998 he and Venter were closing on a deal that would once again transform conventional genomics researchlinking the medical giant Perkin Elmer and Venter's expertise to go after the human genome for a fraction of the cost of the government effort. They would build a whole new institute up the road and call it Celera after the Latin celer, meaning swift. The pace was increasing so fast that even some of Venter's closest colleagues felt it. Venter's secretary Lynn Holland kept the balance on the flying projects. "I'll get a call when he's on the plane and it'll be, uh oh, Craig has another idea." Not wanting to repeat the mistakes of the past, Venter and Hunkapiller called in NIH's Francis Collins, who had taken over the government Human Genome Project from James Watson. On May 8, 1998, Venter called Collins to meet the next day with them at Dulles Airport. There, the two moved fast. They told Collins they were forming a joint venture to use Perkin Elmer's ABI 3700 machines to pursue the human genome. They thought they would succeed in a maximum of two yearsand did not want to upset the government project, which was projecting a seven-year deadline. Collins was a little nonplussed. But three days later, a press conference was called to announce the formation of Celera to pursue the human genome in competition with the government's consortium of eight universities and the Sanger Center in England. Collins appeared on the panel, looking uncomfortable. "I don't think these two efforts will compete," he said gamely. "I think there's room for both approaches." Indeed many critics were claiming that Venter's approach was too fast, too haphazard, to get an accurate genome. Venter countered that Celera's genome, made with what was described as a "HAL-size computer," would be even more accurate than the government version. "When you hear arguments that what we are doing here can't work," he said, "it's just because it's beyond the imagination for most scientists . . . dealing with tens of millions of pieces of DNA at a time and having a computer solve all these massive calculations." Celera was an incredible leap in capability, and the human genome was only part of a grander plan to sequence a thousand major species in the next decade, laying the foundation of an electronic information

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empire. By now the world had heard much of such leaps. Venter sailed his yacht Sorcerer in the Newport to Bermuda yacht race, the sail sporting an image of his face wearing a wizard hat. He went on a whirlwind speaking tour, beginning with an invitation from an old nemesis, James Watson. Speaking at Cold Spring Harbor, Venter was criticized for the "quick and dirty" approach Celera was taking. "Far from us being the evil empire, we as a corporation are providing them with the tools and reagents," he responded to The New York Times, "to try to compete with us." As work progressed, he traveled to address the Nobel committee in Stockholm. He traveled by rented jet to countless trade shows, talking about the new era of the genome and arranging potential deals. He met with Smith Kline Beecham, at an exposition called Bio '98 in Manhattan. Someone asked him to dance in a tophat with two girls on stage, and he refused. "There're some things I will not do." By October, Celera announced yet another link, this with Compaq computers, which would provide the hardware for the human genome search. The burden of Celera's speed fell once again on his group. Tony Kerlavage helped coordinate the efforts of three hundred ABI 3700 machines. He gave a talk at a chaos-inspired session at the American Association for the Advancement of Science (AAAS) conference in January 1999, in Anaheim. The session's title was "Managing Massive Data Sets in Mathematics, Science, and Technology." When I saw Kerlavage there, he spoke of the frantic pace. "It's . . . been interesting," he said of his past few months, We chatted in the bookstore, where I bought gifts for my nine-and eleven-year-old children. "Here," he said, handing me a book. ''This is a good one." The title was Perspectives on Genetic Patenting: Science, Religion, and Industry in Dialogue. Later, in 1999, Celera collaborated with several universities in completing the genome of the fruit fly. Anticipating the historic day when the entire human genome was completed, Venter planned to make a "consensus human genome" available to the public on a DVD disk, and to give academics a cut-rate subscription for the full database. The commercial rate for access, however, was pegged at $5 to $10 million a year. The uncertainty in the planned subscription fee suggested the risk of genome investment.When the government group finally finishes, by contrast, its database will be free. For all the hoopla, the genome projects were mainly a start to the much more complicated ongoing work of understanding how genes operate. "We're attempting to understand the essentials of life," said Venter. "It's like coming into a dark room and turning on a light so you can see."

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9 Genetics has advanced at such a dizzying pace, with new genes being identified almost daily, that it belongs to myth: as science it thrives as metaphor, as a spur to see the world whole. The pursuit of gene function will overtake gene indexing as today's race. Predicting or treating disease with genes is unbelievably difficult. So many factors are involved, so many mutations, chemicals, processes, and fail-safes, that we are barely beginning to see some of the pathways by which disease develops. Researchers are using their new tools to shift away from looking for single genes responsible for disease (like cystic fibrosis or sickle-cell anemia) to identifying genes that contribute along with other factors to more complex diseases (like Alzheimer's, diabetes, and heart disease). Complex diseases are not caused simply by single genes, but by a combination of genes and environment. What does the genomics revolution mean? If we could learn how a body uses its DNA library to attack an unknown disease, for instance, the savings in drug manufacturing would be tremendous. It means perhaps a cure for cancer or AIDS and unassailable solutions to unsolved crimes. It promises new understanding of the evolution and essence of life on Earth and elsewhere in the cosmos. Much of our so-called "junk" DNA is not junk, for instance. It carries a history of lost genes in much the same way a writer keeps basement files or an overcrammed closet where rediscovered ideas can spur fortunate inventions, species improvement, evolution. Like its pursuers, DNA is a consummate multidisciplinarian and opportunist, a plagiarist of good ideas. Most of all, the current upheaval means a fundamental change in the philosophical assumptions of genetics. Once thought to be a dry process governed by Mendel's laws, today inheritance is seen to be incredibly fluida universe governed by accident and will. Unlocking the whole genome, researchers now see life as a million chemical pathways through a labyrinth of tendencies, statistical probabilities, and sheer inventiveness. "Having the human genome sequence will force a fundamental change in the way we think about every other biological problem," says Mark Adams. A new interdisciplinary approach has given rise to a new fundamental approach to science, with most of its innovations coming from researchers outside the envelope of their fields. Venter's contribution was to see the connections. He did not invent automated DNA sequencing, Leroy Hood did. He did not make it work, Jeannine Gocayne

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did. He did not create ESTs, Mark Adams did. He did not build the TIGR Assembler, Granger Sutton did. He did not build the library to sequence the first full genome, H. influenzae, Hamilton Smith did. He did not create the incredible computer flowcharts for assembling the human genome at Celera, Tony Kerlavage did. What Venter did was something none of these people could do: he envisioned the relations among computers, sequencers, established libraries, and unknown organisms to glimpse each next wave before it happened. The steps that he took would be repeated countless times, in many fields of science almost simultaneously. They included his interdisciplinary approach, bringing in biologists like Adams, computer scientists like Sutton, and technicians like Jeannine Gocayne. Perhaps Venter's inability to see a mental picture is complemented by greater creativity in intuiting precisely the technological links that will work. He described this skill as intuition. "I just saw in a flash that the breakthrough was in linking the machine to the computer, applying remote sensing to basic artificial intelligence." Exponentially upping the power, he achieved a synergy that made it possible to take on the whole genome itself. It could be simply that he was the first to imagine such a possibility. Like the medical corpsman working with what he had in a Vietnam battlefield, he had taken the most pragmatic approachmixing existing technologies and pushing to get the most out of what he had. The investor Wallace Steinberg considered himself an intuitive thinker, and he likened Venter's intuition to having a dozen computers working on a single problem in parallel. Venter had many of the other clichéd elements of intuitionvision, trust in his ideas, the ability to foresee which wave to ride. But most of all he would not let colleagues let go of a dream. Like each of the researchers to follow in this book, Venter pushed science to a process-oriented outlook. For all of the controversy, Venter was always open to the public, willing to take his time to answer questions about his work. He read widely, thinking about the larger implications of the gene revolution, and convened a special ethics panel when it seemed the possibility for engineering life forms was worth pursuing. He relished books like E. O. Wilson's Consilience, on the future link of science and the humanities, and Anne Sayre's Rosalind Franklin and DNA, about the forgotten woman in the gene quest. He raced his yacht,whose largest sail he decorated with a huge drawing of himself in a wizard outfit. His was an American story, and he often repeated the idea that the support for his innovation was only possible in this country.

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Venter also learned how to manage a laboratory from the mistakes he had seen Nathan Kaplan make. He put together the backing that allowed him to go outside the National Institutes of Health and the National Science Foundation, essentially bureaucratic institutions bound by political agendas. It could be that this trick of managing without losing the upstart edge is his greatest accomplishment, a requisite of complex-systems science. By contrast, maintained Cameron, "Watson and Crick's achievement was simple. By the early 1950s someone was going to get the double helix. Linus Pauling was close. What Craig did is far bigger. No one was close to pulling together the backing and intuition to pull off shotgun sequencing. No one had imagined it." What is the relation between such imagination and a personality? When the history of twentieth-century biology is written, it could well be that the humble connection of small and large, theory and practice, computers and biomimicry, harnessing RNA to do a researcher's work, will stand out as a much larger and symbolic innovation than the discovery of the double helix itself. The new paradigm of biology, rightly or wrongly, has become information. In time, this will change. But for now, DNA is pure thought, good and bad ideas locked inside a microscopic cell. "There's nobody who's been in this spot before," said Venter. "It's the opposite of the end of science. It's really the beginning."

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On the Road: Susan Greenfield and the Magus 1 In 1974 a lanky twenty-two-year-old senior named Susan Greenfield was filling out yet another graduate application in her room in Oxford, England. The Velvet Underground blared from the record player and cigarette smoke hung in the air. Applications to the Royal College of Art, a design school, and a physics program lay strewn about her room. Greenfield had long legs and bright dark eyes with a glint of urgency. A flop of long blond hair hung to her shoulders. She was about to graduate and was trying to decide what to do with her life. It was driving her crazy. She had begun at Oxford as a philosophy major four years earlier, but quickly despaired of the field's endless deconstruction of language. She switched to psychology, but soon felt frustrated by the interminable experiments into rat reflexes. She wanted to pursue big, fundamental questions. She was obsessively energetic and stubborn. "I was really prancing around, applying for lots of barmy courses, not really having much direction," she said. Talking with her tutor, experimental psychologist Jane Mellanby, she kept coming back to her interest in the human mind. Why did we act the way we did? What was the basis of thought? "Well," Mellanby leaned back, thinking. "Wouldn't it be a hoot to be a neuroscientist?" Mellanby recommended her to Oxford researcher David Smith. At the time, neuroscience was in its infancy; Oxford had one of the few doctoral programs in Great Britain. Science, it seemed, could

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more easily peer outward to the most distant stars than look inward to the organ that created its own laws. Smith was working in his biochemistry laboratory when Susan Greenfield interrupted him. The room was small and drab, the hallway outside painted a dull green. She told him she was fed up with psychologists and philosophers treating the brain as a black box. She wanted to unlock the processes that made it work. She glanced at his worktable. "What are you doing?" she asked. "I'm working on acetylcholinesterase," Smith said, in his precise Oxford accent. "What's that?" she asked. "It's an enzyme that breaks down acetylcholine." He watched her. "Do you know what that is?" "I think so," she said, "It's released from nerves." "Do you know what the reaction is?" "I don't have any chemistry." Smith paused. The whole point of neuroscience was to analyze the chemistry underlying human thought. But though he looked like a typical researcher in his wirerim glasses and his portly white labcoat, he could appreciate the quirky bit. He was willing to listen as Susan Greenfield took a deep breath and began. Neuroscience had contented itself for too long with minor questions, she said, while the strict boundary between it and the humanities held research back from the really important thing, consciousness itself. She talked fast, jumping from idea to idea. "But she had a vision," he recalled years later. "She knew what she had been taught wasn't the right way, and she wanted to find the new way." Smith decided to send her to the department chair, Sir William Paton, a distinguished, slightly balding, pipesmoking archetypal Oxford don. One of the last great scholars of science, he read Plato and asked tough, penetrating questions. After grilling Greenfield, he called on Smith. "What do you think," he asked, "about Susan Greenfield?" "I don't know, what do you think about Susan Greenfield?" She was a huge risk is what he thought. But Oxford made a point of encouraging people to take such risks. The system required students to talk to faculty from other disciplines. Around each Oxford college dinner table there sat teachers from the sciences and humanities, taking the time to talk and listen and confront each other. Taking a risk on the quirky or eccentric, the difficult, the lost, was what Oxford was all about. So, they decided to take a risk. On Susan Greenfield. <><><><><><><><><><><><>

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Until recently science said very little about the mystery of consciousness, even though philosophers had filled libraries with books on it, and even though science could say a great deal about the three-pound, moist and soft organ that creates it. Research into the brain had been going on for hundreds of years, fascinating especially those with a creative bent. Craig Venter began as a neuroscientist. Later, the young physicist Saul Perlmutter haunted neuroscience conferences. But the self presented such a deeply complex problem, beginning with the fact that every human self was different, that serious researchers ultimately gave up on it as unknowable. Perhaps for that reason, brain research's early breakthroughs had come by accident. In the late nineteenth century the researcher Nicolai Golgi, for instance, accidentally dropped a slice of a human brain in a jar of sulfur nitrate. Discovering the lump two weeks later, he found thousands of tiny branches stained blackish by the nitrate. He called them "neurones." The field of neuroscience was born in mishap. In the following eighty years a host of findings, accidental and planned, began to unlock the electrochemical pathways of neurons. As researchers pursued the intricate details of brain wiring and activity, they learned that, if a supercomputer tried to replicate all the functions of the brain, it would require enough electricity to heat and light one hundred thousand homes. But as for the big picture, the question of exactly what a thought is, the mind remained as much a black box as it did for Renaissance magicians, who called thoughts "phantasms" and attempted to manipulate them through alchemy, astrology, and a diet of leaves or honey. Consciousness was the ultimate mystery. What is the imagination? How does it work? The ancients believed thoughts were images. Religions placed intelligence in the mind of God. Literary modernists tried to recreate it in "stream of consciousness" passages. Everyone mused about the organ that made us dream or do poorly in school, win a Nobel Prize or embezzle a bank. But no one in science attacked the question of consciousness. It was too big, too slippery, too . . . dangerous. Taking it on would require a new kind of research involving many disciplines linking complex electrophysiological and biochemical systems with the abyss of the emotions and even individuality, trying to chart the chaos of whim and logic. By the middle of the 1990s, however, the time was right. Science exploded with big theories and bigger egos, attempting to do just that.

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2 At first glance Susan Greenfield might seem an unlikely candidate for a leader of the first wave of a new complexsystems science. Her father's father came to England from a Polish shtetl, ran a chocolate factory in London's East End, made and lost a fortune. Her mother ran away from an upper-class boarding school to become a chorus girl. Her father had a "spirit," she said. "Things sort of fell out of the sky. He never really connected with the work ethic too much." Her mother was Church of England, her father Jewish. Both were deeply curious, big talkers, and "very carpe diem," she recalled. Born in 1950 in London, Greenfield was older than her brother by thirteen years. Her mother was theatrical, given to asking sweeping questions like: "Is the red I see the same as the red you see?" Her father was an electrician who gave her a tinkerer's confidence in thinking a problem through. Growing up, Greenfield felt like an outsider. When she wanted to wear a cross to school like her friends, her mother made her also wear a Star of David. They were on the low end of middle class, and, though her school friends went on foreign holidays or were chauffeured home, Greenfield found her solace in the county library. In high school, or A levels, in west London, she studied Latin and ancient history. She took ancient Greek from a teacher named Veronica Lemon who became one of her early mentors. Greenfield loved discussing questions like why do people go to war, why fall in love? She found her answers in the classics. She devoured The Bacchae of Euripides, for instance, relishing its identification of our animal and human natures with the forces of wine and bread. She also had to study mathematics, rigorously. Energetic, passionate, flitting from subject to subject, she earned the lifelong nickname Springy from her friends. "The training to seek motive came from the humanities," she later said of her education, "and steel-trap proof came from mathematics." She won a place to read classics at Oxford's St. Hilda's College, the last women's college at the school. Lying just over Magdalen Bridge on the grassy bank of the River Cherwell, St. Hilda's had a strong literary tradition, with author Barbara Pym as a tutor and students who became leading critics of postmodernism. Greenfield joined an adventurous group of women who clamored in argument over cheap bottles of wine on the dormitory steps on winter evenings. In the evening, students and faculty rode by on bicycles on the cobblestone streets as the smell of dried leaves and dinners rose in the air. Their traditional black gowns billowed in the dark over hooded sweatshirts and jeans.

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Finding philosophy at Oxford too linguistic, she approached Jane Mellanby about psychology. "My first impression was of a very enthusiastic and extremely scatty person. She was speaking about all different things at once," recalled Mellanby. Mellanby got her started in a crash course in basic science. But Greenfield soon found psychology to be wanting, too. "It was all rats pressing bars. It was very vague, with no hard science." She nevertheless produced an impressive undergraduate thesis. "She brought together physiology, anatomy, and behavior. It was very original," Mellanby recalls. ''People weren't doing that much then. It was bold and unusual." Accepted into the doctoral program in neuroscience, Greenfield worked in a third-floor laboratory of the cramped pharmacology unit. Her shared lab room smelled of formaldehyde and ashtrays, but it looked out on a lone, beautiful copper beech tree. She had to work twice as hard as everyone else. She stayed up late at night, building a two-pack-a-day smoking habit as she pored over organic and inorganic chemistry texts. A few people made fun of her. An obnoxious Australian mocked her constantly. She borrowed the department's textbook on acetylcholinesterase and spilled coffee all over it "much to every one's annoyance," recalled Smith. But she turned her weakness into a strength. "I studied longer and I took a broader view than others," she says. "I wasn't afraid to say, I don't understand." Her work paid off: by her second year, she applied for and won a general scholarship at St. Hugh's College. She found the Australian and "gave him two fingers," she recalled. As her parents had lived, so she followed her instincts, drawn by the unusual, the nonclassical, "the odd bits, like an obscure enzyme secreted by a neuron," she said. Such interest in the "odd bits" had of course led to many science breakthroughs in the past, like Bernoulli's seventeenth-century models of coiled wires that led indirectly to the modern calculus of variations. She followed up on Smith's work on acetylcholinesterase, but "she knew how to take it further," Smith observed. The story of acetylcholinesterase offered a parable about a researcher following his instinct. The enzyme had been discovered in 1914, when the English scientist Henry Dale could not figure out why the effect of the nerve transmitter acetylcholine on the heart and other muscles was so short-lived. Rather than assume his experiment was being done incorrectly, Dale had a flash of insight about the ways nerves signaled each other, one "which was absolutely crucial if the signals were to be clear and unambiguousthe immediate destruction of the transmitter chemical once the signal was sent," Greenfield later

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wrote. The neural transmitter acetylcholine was broken down by acetylcholinesterase. The story of Dale's faith in his intuition made an important impression on Greenfield. By the 1980s acetylcholinesterase was commonly regarded as a protein tightly bound to the cell membrane, whose main function was simply to kill the messenger acetylcholine after its message was sent. The Nazis had used it to develop the nerve gas sarin, which blocked acetylcholinesterase and thus paralyzed its victim. Before Greenfield joined the group, however, Smith and an Australian colleague Ian Chubb found acetylcholinesterase in the cerebral spinal fluid, suggesting that it must be released by neurons. "This was a heretical idea," Smith recalled. "Nerve cells were not thought to release proteins at all, they were just thought to release the small neural transmitters," he said. "The idea . . . was just completely way out." Smith more or less stopped there. But Greenfield, with her background in experimental psychology and her passion for odd bits, wanted to know what acetylcholinesterase could be doing so far from where acetylcholine played a role. Greenfield's pursuit of the second function of acetylcholinesterase became her doctoral thesis project. She decided to put electrodes into the brain of a rat to see if she could get neurons to release acetylcholinesterase directly. To do so, she needed to learn electrophysiology, which brought her to the office of John Stein, a vision expert at Magdalen College at Oxford. The son of a major industrialist, Stein became a close friend, mentor, and fellow poetical seeker of truth, who stayed up late into the night talking with her about the artistry of science. He taught her the delicate technique of implanting electrodes in a cell and sending a pulse, enabling the researcher to measure the imbalance in ions by which nerve cells created an impulse. She never became very good at the technique, but she learned well enough to show something startling: parts of the brain rich in the enzyme acetylcholinesterase secreted a certain important protein in massive doses, and the other parts did not. "It was innovative," Smith observed. "It seems obvious in retrospect, but it wasn't at the time." Greenfield had shown the ability to branch out into a new field to deal with a problem that more senior researchers evaded. "She could see very clearly the simple experiments to give the answers. Not the unnecessarily complex sophisticated stuff," Smith said. "You have to have a knack for peering through all the fog and see exactly what needs to be done. Susan had it." Yet she was only beginning. "I want to prove this protein does something in the brain," she told Smith.

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"Why do think it does anything?" he said. For him it was enough of a surprise that nerve cells secrete proteins, but to think that the protein had a larger function was extraordinary. She thought acetylcholinesterase, the signal destroyer, held a crucial secret to brain function, to development and disease. If it was crucial to development, she speculated, then it might also play a role in degeneration. She wanted to explore its effects by squirting it directly on neurons and studying what happened. This would be extremely difficult. To do it she needed to learn about the biochemistry of the nervous system almost from scratch. "I thought she was crazy," Smith said, "but I didn't say so. I thought, if she wants to do it, let her do it." After earning her doctorate in 1977, she produced two major publications demonstrating a link between acetylcholinesterase and the brain signaler dopamine. Dopamine was central both to brain development in an infant and to its degeneration in an elderly person, as well as to Parkinson's disease. She found reassurance for her focus on the obscure enzyme, which few others were following, in a book by researcher Anne Silver that speculated that acetylcholinestrase could be a key to brain signaling. Greenfield was not afraid to go out on the same limb. "Surprisingly few scientists are happy to take risks," she recalled. "If you say anything about me, say that I took risks." She wanted to understand what was going on with acetylcholinesterase at the molecular level. "She had imagination," observed John Stein. "That's not mere instinct, not mere intuition, that's how science works. Or good science." 3 In a lecture hall at a neuroscience conference in Lausanne, Switzerland, Greenfield sat in the audience talking to her graduate student about the recent discoveries about dendrites, the filament-like branches of neurons. She was saying how important it would be to understand their chemistry when a small, white-haired man in front of her turned to her. He was one of America's premier neuroscientists, the Colombian-born Rodolfo Llinas. At New York University, Llinas was developing sophisticated

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electrochemical techniques to map the brain's activity. "Come to New York," he said to her. She did come in 1981 and 1982, spending most of her money to live in a closet-size apartment near the United Nations on Manhattan's East Side. She dodged derelicts on her way from the lab. She made few friends and very little money. She learned a lot from Llinas, especially about paying attention to the way brain regions interacted. It was a difficult and exhilarating time, a "rollercoaster," she later recalled. Watching Llinas, she saw a top researcher willing to tackle big questions, making mistakes but moving on. "We worked very hard, and he made me think very hard and then challenged what I thought," she recalled. It was a struggle, but she finally succeeded in developing a new technique for measuring acetylcholinesterase on-line, in the brain, using a light-emitting chemical. For his part, Llinas was impressed. "She was very young, just beginning, but she was very smart. She knew her biocemistry. And she was hell on wheels, always ready to try something new. I think she was very strongly influenced by her time in the United States," he recalled. "She saw a different rhythm than in Europe where science was more restrictive, and the emphasis was more on being a professional science accountant rather than a true explorer. We discussed this a lot." Llinas took her to New York's exclusive Century Club, encouraging her to practice science that took risks, even if "you end up with egg on your face. If you reach for the stars," he said, "you'll never get lost." By the end of her second fellowship, she had changed considerably. She owed a great deal to Llinas but also chafed under his ego as she gained more confidence. She admired him yet found him "caught by his own vanity." As the heat grew and new leaves uncurled in Washington Square Park, she began to focus her diverse interests. She was coming, forcefully, into her own. Most important, by 1982, she was publishing, in Nature and other leading journals, three major papers charting the important "novel" functions of acetylcholinesterase. With these, Susan Greenfield made her debut. When she returned to Oxford, Smith was amazed. "By God, she showed acetylcholinesterase affected nerve cells in a sophisticated way. It caused ion channels to be opened, which may be a good thing in small amounts, but if you have too much of it can kill the cell." She was showing what she had speculated to Stein, that if acetylcholinesterase played a key role in development, then it also played a

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key role in degeneration. Greenfield saw it could be related to cell loss in Parkinson's disease, and could be exploited for an improved therapy. At that time, though profit-driven research on Alzheimer's and Parkinson's was growing intense, only two other, Latin American, researchers saw the intuitive connection she was making. She now had her own small lab. As a postdoc she had contracts with no teaching obligations. She woke at 5:30 AM and worked until 11 PM, unless there was a party. To unwind she hung out at the King's Arms, with its rugby scores on the walls of smoky, warrenlike rooms. It was the happiest time in her research life and the most pressured: she had to build a track record fast. Greenfield's push for an interdisciplinary approach to the prize of thought itself made her something of an outcast. "I can't understand why you're not interested in consciousness," she told Smith, who was becoming more of a rival than a mentor. "It's not that I'm not interested. It's just that it's so far away from understanding," he said. In 1983 she was eating in a Chinese restaurant in Oxford with philosopher Susan Hurley, the wife of a friend. Discussing their research problems, they saw they were climbing "the same hill, but from different directions." They hatched an idea for a series of lectures on consciousness by the world's top names from the humanities and sciences. Even though the series was not formally announced, it drew an overflow crowd every month. Famous thinkersthe University of California's John Searle, Oxford's own Roger Penrose, and Llinas himselflectured and allowed their papers to be collected in a book, Mindwaves, coedited by Greenfield. Published in 1985, it presaged the coming interdisciplinary, complex-systems explosion in the field and in science generally. For Greenfield, it meant more. "I had come full circle back to my original interest in philosophy and the Greeks. I'd spent all these years out in the wilderness, doing nuts and bolts stuff, and I was now in my thirties and feeling much more confident." Such a one-two combination, strong science and strong arts, small picture and big, marked her career from then on. With the book in hand Greenfield applied for a medical professorship at Lincoln College. It was a prestigious post, like that of associate professor in the United States. "Oxford is peculiar in this regard," said senior chemist Peter Atkins, who was on her review committee. "Everyone has two jobs herea university lectureship, and a role as tutor in a college." Atkins was impressed by her rigor as a tutor. Here was someone who had been forced by ignorance to work hard and expected her students to do the same. "She would take a tough line, which is what Lincoln's medical students need," he said.

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Election to the post of professor put her in the elite of her profession. She was regarded with authority but still wore her black leggings and high Parisian black boots, her striped tights and bright pink tops. Lincoln, with its august tradition, was not used to someone like her. Howard Walter Florey had isolated and purified penicillin at Lincoln College, winning a Nobel Prize and giving birth to the age of modern antibiotics. Her office sat at the top of a rickety wooden staircase, attached to a private reading room that provided the day's newspapers, fresh fruit, cheeses, and sherry. The professors' meals were prepared sumptuously. Greenfield chainsmoked, arguing over dinner at high table with Atkins, a chemistry researcher whose texts had been translated into some twenty languages. They sat with other faculty in the great oak dining room, built in 1427, which had a hole at the apex of its vaulted wooden ceiling for the original cooking fires. Atkins disliked her smoking and disagreed with Greenfield's theory of consciousness. She believed thought was profoundly deeper than what a computer could ever do; he argued that machines one day would think better than we did. In a computer, she replied, a switch is either on or off. In the brain, there are many differing grades of "on" or "off." Neurons could be very receptive to electrochemical signals, slightly receptive, or not receptive at all. Also, neurons in different locations of the brain were involved with the same thought processes. The reductive link of region to functionthe left-brain, right-brain crazewas completely misguided. While some regions roughly corresponded to certain functions, the mind was much more subtle than mappers let on. If the brain lost one function, like sight in one eye, it rewired itself to use different regions and make up for the loss. Consciousness was in her view generated by shifting groups of neurons firing by the tens of thousands rapidly all over the brain. She called these neurons "assemblies" and urged her colleagues to look at how they differed in different people. "For most scientists, subjectivity is the dirtiest word," she says. But you could say nothing substantial about consciousness, she felt, until you could explain why everyone is so different. At the same time, she pushed her work on acetylcholinesterase. "She was fighting a lone battle. People just thought she was . . . a little crazy," Smith recalled of her ideas about the brain chemical. "She'd published in peer-reviewed journals but for ages she couldn't get any funding from government sources, partly because people just," his voice lowered to whisper, "couldn't really believe it."

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4 In the late 1980s, Oxford's way of life, at least its struggling pharmacology lab, was under assault. For a few years, pharmacology was slated for removal altogether. Greenfield and Smith scrambled for money. Smith talked to numerous corporations. The directors of Squibb, Britain's enormous pharmaceutical company, asked him to organize a neuroscience symposium so they could understand the field's financial promise. Along with other members of the department, Greenfield presented her research on Parkinson's and Alzheimer's diseases. "She was the one," Smith told me, "who most impressed them." Greenfield joined Smith in the negotiations with Squibb. There was an enormous potential drug market among aging baby boomers, if her ideas were correct. Greenfield excelled at putting her ideas before an audience. "She made connections no one else saw," Atkins said. "Albert Szent Györgyi, a Hungarian biochemist, once said science consists of seeing what everyone has seen, but thinking what no one else has thought. That was her ability," In 1987, in exchange for intellectual property rights to the work of its neuroscientists, Squibb gave the Oxford University Pharmacology Department twenty million pounds, the single largest university grant ever offered in England. Critics leapt on the grant, claiming it was a Faustian pact that traded off a scientist's objectivity for a sleek office. "In fact, it takes so long for papers to be published," Smith responded, "that we have never had to delay publishing a finding to suit Squibb." There was nothing new about patronage of science, and Oxford merely got on the biotechnology bandwagon early. "In the old days you didn't need very much money, you could be very scruffy and deliberately inefficient. I don't think that works any more," Greenfield said. Galileo after all, father of modern science, called the moons of Jupiter he discovered the "Medicean stars," after his wealthy benefactors. The accelerating discoveries in the mind led the last years of the millennium just past to be dubbed the "decade of the brain." Top researchers raged over consciousness, flinging enormous books and egos and theories back and forth. On one side were the "physicalists," like Tufts University's Daniel Dennett, who thought of neuron assemblies as "multiple drafts," MIT artificial intelligence expert Marvin Minsky, who was trying to build a machine to think, and Rodolfo Llinas himself, who saw consciousness as simply one of many products

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of routine electrochemical impulses. On the other side were the "mysterians," including physicist Roger Penrose and evolutionary psychologist Steven Pinker. They saw consciousness as more like tragic mystery, a sum greater than the parts of neurons and physiochemistry, infinitely beyond the capability of a machine. The field was in crisis. Bernard Baars, a psychologist at the Wright Institute, in Berkeley, California, compared the chaos to the state of physics right before Newton. Greenfield's theory of consciousness showed the quality of compromise, incorporating elements of many sides of the debate. Unlike most of the giant tomes that were coming out, her book Journey to the Center of the Mind was short, clear, fun, and sensible. Writing it as a form of relaxation on weekends, she moved easily past the de rigeur disquisitions on Plato to stake out a middle ground. She saw the mind as something like one of the conferences she chairedwith disparate concentric groups of neurons ignited at different times, their attentiveness or receptiveness ebbing and flowing, forming changing assemblies. Beautiful electrochemical images of the brain showed fleeting electric patches or networks of thousands of neuron branches firing as a mind listened to a single sentence. She insisted that science pull apart the processes by which these neuron assemblies formed and changed. This made her a mysterian, but more: an artist of complex systems, in the way that neurologist Oliver Sacks called for science to restore the humanities to its core. Reminding scientists that no two minds thought alike, she repeated her claim that consciousness research could claim no victory until it said something about individual differences. Virtually no one in science had taken up this overarching problem. For the mentally ill or hyperactive children, medicine was making seemingly great, profitdriven strides with psychotropic drugs, but no one really understood why Ritalin, for example, worked differently in different people, nor why the same neurotransmitters in healthy minds create our different personalities. Science had reduced its vision too narrowly. Mind and emotion, rational and irrational, were as inseparable for science as they were for Euripides. "A computer cannot think because a computer cannot feel," she wrote. "The problem lies in the strategy that, by building machines that get better and better . . . the missing ingredient, the feelings that are the essence of our awareness will somehow materialize. It is like adding ingredients to an increasingly subtle and impressive curry, in the hope that the taste will spontaneously emerge as that of Baked Alaska." This realization was the critical step into the new science of complex systems that she would champion.

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At Lincoln College, Atkins's and Greenfield's arguments over consciousness had the "happy quality of being without resolution and so they could continue every night," Atkins recalled. First they were seated next to each other by chance, and "then by design." Meeting at meals solved the problem of going out on dates, and they married in 1992, In a tiny village registry office, Atkins's daughter from a previous marriage served as best man. Greenfield's younger brother, whose childhood fear she had explored in her book, was chief bridesmaid. Their honeymoon was to take one day off. But Susan Greenfield did make one key concession: she agreed to stop smoking. 5 In 1994 Greenfield appeared on a late-night television discussion "only one man and his dog would watch," she says. Attractive, quick-witted, she caught the attention of the Royal Institution, England's premier body dedicated to the communication of science to the public, dating back to 1799. Every December the Royal Institution chose a leading scientist to conduct its televised "Christmas Lectures" for children. Past lecturers had forged an important British tradition, featuring such personages as the Institution's founder Michael Faraday, the astronomer Carl Sagan, and, more recently, Oxford naturalist Richard Dawkins. That year, Susan Greenfield became the first woman in history to give the Royal Institution Christmas Lectures. She was a huge success. That success led to a BBC series and a popular book on the brain. She had also begun writing a regular newspaper column for The Independent, a task she would complete on "Sunday afternoons, as other people might take up gardening," she said. "It helps me see the wood for the trees." In her column and public lectures around the country, she weighed in on such topics as discrimination against women and the need to combine disciplines to pursue consciousness. She was enthusiastic and inspiring in a "vivid, imaginative way," commented The Times. Her communication with the public also energized her research, her graduate student Steve Emmett noticed, by forcing her to slow down and simplify. In early years "she talked so fast people

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in the group could not keep up," he recalled. "Now she had to become more understandable. It was good for the group." In her articles and appearances she did not merely perform: she put a researcher's thought process on public display as it unfolded. When she attended a conference session that made her disagree violently, her readers knew about it. When an ugly rumor about a female scientist was passed to her, her readers knew of the offensiveness of rumor mongering. When writing for TV made her realize the importance of metaphors in scientific theory, her audience learned as she learned. When September rolled around and she thought of the time consumed by one-on-one tutoring with undergraduates, her readers learned of the value of teaching in research. At the second annual international conference on consciousness at the University of Arizona, in 1996, which drew over a thousand delegates from a number of fields, Greenfield spoke on a panel that included Rodolfo Llinas, telling her readers other revelation there as to why computers would never be as smart as humans: "No computer can laugh, or fall in love, or feel remorse. . . . To me, emotions are the building blocks of human mentality." Writing as she lived, on the go and out loud, was a high-wire act in the style of Beat writer Jack Kerouac. She pushed herself by purposely going out on a limban uncomfortable place for most academics. "It helps me keep the wider perspective other researchers lose," she explained. Her public persona also left her exposed at times with what might seem foolish or imprecise ideas out in print on the World Wide Web. "I love venture capitalists," she once said. "They're the swashbuckling pirates of our time." At one website she was quoted as worrying about evildoers "hacking" into someone's consciousness. She contributed ideas to a CD of songs to take to a desert island (her selections included I Heard It Through the Grapevine, Brown Sugar, and Non, Je Ne Regriette Rien). This willingness to become a public pundit, and her success with it, enraged some of her colleagues. "Scientists . . . are nervous about speaking on anything that is outside of expertise, whereas media people stray across a wide range of subjects," she told The Times."When they ask, I always say yes.'' She fed on the delight of curious minds that did not take themselves too seriously. While the audience for such fun, and creative, mulling about science had been there as long as science, electronic outlets were exploding. Greenfield suddenly became perfect for her historical moment. In 1989 her fellow English researcher Stephen Hawking, having labored a long time to produce the beautiful if somewhat unintelligible book called A Brief History of Time, saw it

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become a huge international bestseller. The audience for the Star Wars movies, the popularity of science books that followed Hawking's, and the rise of cable television channels such as Discovery, and The Learning Channel, as well as the World Wide Webwhere the 1996 Mars Pathfinder mission site quickly became the most viewed website in historyall created opportunities for science pop stardom in the 1990s. Few had seen a scientist like Susan Greenfield before. Greenfield's public outreach not only raised science's profile in Great Britain, it also helped her to step back and see the big picture. One rainy Sunday afternoon (British science owes a lot to a climate that encourages introspection), she stretched out on a couch in her countryside home and jotted down the recently discovered features of acetylcholinesteraseits role in Alzheimer's and Parkinson's diseases and fetal development, the fact that in fetuses acetylcholinesterase had the same form it had in Alzheimer's patients but different from that in normal mature adults, its perplexing way of popping up in different regions of the brain. In a series of elegant experiments with rats, Greenfield had seen acetylcholinesterase disappear in the extracellular space around the substantia nigra, a microscopic brain organ vital to movement. She knew, of course, that the chemical was related to muscle function. UCLA researcher Nancy Wolf, writing about global neurons unlike neurons of any other area in the brain, noted that global neurons shared one featurethey all contained acetylcholinesterase. Looking at her list, Greenfield felt more than ever that the chemical was a key to brain health. The difference now, with her Oxford professorship, media success, and a series of increasingly convincing results published in peer-reviewed journal articles (eight in 1995, seven each in 1996 and 1997), was that she could mobilize resources. As her audience widened, her research intensified. Typically, she turned to another field to take the next step. A year earlier she had approached her Oxford colleague, cell biologist David Vaux, for help in developing a technique for tagging acetylcholinesterase with a fluorescent dye, to track it in the brain. As Vaux grew interested in her work and in the new discipline of comparative genomics, Greenfield suggested they join forces. Using their different fields of expertise, they began looking for the part of the acetylcholinesterase molecule responsible for its unknown functions. Perhaps it could be responsible for the way Alzheimer's and Parkinson's diseases killed brain cells. With some modest early success, Greenfield talked to Sir Martin Wood, director of Oxford Instruments, a private company that helped

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Oxford researchers develop ideas with the backing of venture capital. He and colleague David Thomas encouraged her and Vaux to outline a draft patent application for a peptide they had begun isolating and suggested that they form a company to go after Alzheimer's and Parkinson's. By December 1997, Wood had raised six hundred thousand pounds for their research, Greenfield and Vaux's company, Synaptica, was born. She enjoyed the deal making, excelling at its required clarity and bluster. "With venture capitalists, bankers in the city, captains of industry, publishers, politicians also, one has to become multilingual. I found that very challenging." Many other start-ups around the world were seeking a cure for Alzheimer's and Parkinson's diseases, anticipating the profit from an aging baby-boomer generation. The difference was that Greenfield convinced her investors and the public she could do it by focusing on acetylcholinesterase. The drug giant Pfizer had just launched a new acetylcholinesterase inhibitor for Alzheimer's. "They have spent absolutely millions but they've not been novel in any way," said her assistant Steve Emmett, one of the first people hired by Synaptica. "Tacrine was the standard acetylcholinesterase inhibitor for Alzheimer's. They've modified the drug chemically and tried to make it better. They're not trying to make a breakthrough whereas people like us are having to be intuitive and insightful. That's the only way you're ever going to cure a disease." Starting with a handful of people, Synaptica grew "like a hydra" said Vaux, bringing in young researchers from multiple disciplineselectrophysiology, molecular biochemistry, genomics, animal behavior. They occupied part of the third floor of the new pharmacology building, the labs close to each other to encourage communication. They met weekly to discuss their workseeking molecular binding sites of acetylcholinesterase, synthesizing peptides and testing themleading to the biggest question: What, exactly, could they market? "We start off a lab meeting from a reductionist point of view and then build up to what we're really seeing with our animal models, and then we'll build a hypothesis," said Steve Emmett. "It works really well." The reason was Greenfield's knack for finding the right path. ''Springy's intuition is legendary," says Emmett. Because of her breakneck pace, though, other researchers began to take pot shots. The University of London's Michael Lacey challenged her findings on acetylcholinesterase. A few of her younger researchers and postdocs, listening to her glowing talks, found Greenfield too idealistic and cheery about the depressed state of science in England. She could be difficult, too, if you were not getting

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results. But she worked harder than most of her competitors. She was working by 5:30 AM and at the office by 7:30. "She doesn't leave until 7:30 at night, so she knows how long you're there," Emmett says. "She sets really tight deadlines." Squarely built, friendly, totally bald, Emmett benefited from her intuition. The son of a Royal Air Force engineer, Emmett had been a bike racer until an accident sent him plunging into a ravine. His injuries healed, but he gave up bicycling and, one month after the accident, at the age of twenty, lost all of his hair. He was reluctantly considering dentistry as a career when he visited Greenfield at Oxford. Hearing of his interest in natural toxins, she asked if he wanted to go to Uruguay for a year to work on snake toxins that could be used to manipulate acetylcholinesterase (the toxins paralyze victims by eliminating acetylcholinesterase). She told him to think it over. A few months later she phoned to say, well, he had one day to decide. On the phone he said yes, then hung up and panicked. "I studied snakes for two weeks at the London Zoo and crammed from my Spanish phrase book on the plane," said Emmett of the speedy turnaround. "It was fantastic." It also, often, worked. Outside Montevideo, Emmett found a snake called the green mamba, which produces a toxin called fasciculin. It binds to acetylcholinesterase "at a very special location, where most other inhibitors don't," enabling Synaptica to study the enzyme in greater detail. Emmett's success only added to the group's awe of Greenfield's intuition. "If you can have divine inspiration," said Emmett, "I think she's probably got it." 6 Such inspiration, some said, was not all divine. Science is a quest for truth, and while "most sci entists are just beavering away at the details," David Smith noted, "Susan is a visionary who galvanized a field. The risk, and she and I have discussed this, is she's not very good on detail. That's not a criticism, that's just saying there're different ways of doing science. That's why she has a good partnership with David Vaux at Synaptica." Even within her group, Greenfield's bold approach sometimes raised a question when younger people presented their results. "The science

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must be good," Steve Emmett noted, adding: "She's very enthusiastic to see positive results. It can be difficult sometimes to make her appreciate control and negative data. When she does, she is quick enough on her feet to take this data in the context of her global hypothesis." Greenfield suggested that negative data, an experiment "not working," might be a clue to a deeper breakthrough if one shed one's assumptions. Part of shedding one's assumptions was to bring many techniques from different disciplines to big problems. "Because I'd come from an unusual background anyway," she said, "I hadn't been brought up in one thing or another, I could range freely among these different disciplines, smashing through these different barriers, not having the complete difinitive expertise in any one." Like Craig Venter in genomics, Greenfield delighted in rattling traditional science. "The problem is that very few people have any ideas," she said. "Safe is a word that goes much better with sex than science." Assailing one researcher's caution in a journal, Greenfield lambasted his criticism that acetylcholinesterase's novelty might be due to lab contamination. "Whilst one cannot prove that there is no contaminant . . . any more than we can prove that there is not a tea pot orbiting Mars," she wrote for the staid journal Neurochemistry International, "at the very least the scenario is unlikely." ("I loved that one,'' said Emmett.) She criticized New York University's Joseph LeDoux, whose book The Emotional Brain described emotions in rats. "The most interesting thing about emotions is that you're feeling them," she says. "If you're not feeling then that's only reflex and that's all he's got." She dressed in mini-skirts with high heeled Parisian boots, and looked good in them, as if to demonstrate to younger women they need not worry so much about acceptance. "I tell them to take risks. What is the big problem if you are wrong?" Once her secretary gave her pink hair dye as a joke. Afterward, it would not wash out, so she walked around with pink-streaked hair for days. Around her, the arguments about consciousness were reaching a white heat as different disciplines entered the fray. Daniel Dennett despaired when a science journal asked him for a round-up of works on consciousness. The intensity of the debate was "almost ridiculous" he told The New York Times, taking aim at physicists like Penrose: "There's a discipline that is even more ignorant about the brain and even more arrogant than philosophy." John Searle assailed philosopher David Chalmers's book on the subject in The New York Review of Books, saying that both Chalmers and Daniel Dennett made the "same dumb mistake" in assuming there is such an entity as the self, Fueled by promising research into the development of an infant's

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mind, neuroscience played a leading role in the popularity of science in the media. Brilliant, articulate, pretty, funny, self-deprecating, and scathingly critical, Greenfield was the quintessence of interactive science, But there was a danger. Neuroscientist Christof Koch warned, "We're going to be called to account in five or ten years . . . if the results aren't delivered." In June 1998, Greenfield ascended to a pinnacle in science in Great Britainshe was named Director of the Royal Institute, poised to play a leading role in communicating the agenda of science to the public, Reading about it in the paper, her old classics teacher, Veronica Lemon, could not believe that this was the same Susan Greenfield who had loved The Bacchae. The appointment gave her a voice as the premier researcher in the country. "It means prestige and money and power," says Emmett, beaming. Characteristically, she meant to use the role as a way of fostering the big picture, practical dreaming, and bringing more women and students from diverse backgrounds to the study of science. The appointment opened all sorts of opportunities, as did her sixpart series on the brain for the BBC. She and Atkins were invited to tea at Buckingham Palace. The BBC flew her all over the world in pursuit of the best researchers. However, the appointment also brought into focus a long-felt but denied issue. In her early days of struggle, Greenfield would have been the first to deny the notion of sexism in science, but the higher she rose the worse she felt it. "It isn't like someone pinching your bum; in fact it would be easier if it were like that. It's much more insidious and subtle, and it gets worse the higher you go," Greenfield said. "How are you, young lady?" a member of Parliament greeted her at a committee meeting. She wrote in a column about the whispered insinuation that one woman in science "had slept her way" to the top. At a party, a department head introduced her to a student as "one of my professors." If she had been a man, she wondered, wouldn't he have introduced a tenured professor by name? She made sure that there was a mix of men and women at Synaptica, and brought many women up with her. One was her assistant, a single mother of two and former advertising executive who, like her, had a working-class upbringing. "Susan is unconventional," said Sandie Lowe, "and I think she is intrigued by those with an unconventional background, especially if there might be a weakness. She would love the opportunity to nurture that person if she sees that potential. It's kind of a risk thing."

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At the top of her profession, Greenfield's experience of women's difficulties did not end. "The subtle patronizing, or being ignored in committee meetings, or being slightly put down, . . ." she said shortly after learning of her ascendancy. "You would look ludicrous if you complained about it," she said. "You just have to absorb it or try to make a joke of it, but that's very hard," Greenfield asserted on the eve of taking on the Royal Institution, its musty creaking staircase decorated with portraits of the men of science of Great Britain. 7 One of my favorite pastimes as a child was to pause on my walk home from school and retrace my thoughts of the previous quarter of an hour. I loved the dreamlike, bizarre associations that led from fantasies of piracy, to interstellar heroics, to girls. The connections of my thoughts fascinated me. They were clues to a mystery that could entertain me for hours. What is intuition? Craig Venter likened it to the speediest and most powerful of all computers, mixing factors and alternatives boiled down by the heart and mind to the simplest and strongest likelihood. "Connections are what I do," Venter said. The famed biologist Barbara McClintock likened it to a Buddhist form of "seeing," in which the scientist achieved almost a mystical union with the subject. Greenfield detests the comparison to computers. "You might as well compare the mind to a bowl of spaghetti, because it has much more in common with the mind than a computer." Above all, Greenfield's journalistic writing, her theatrical dressingboots, sweeping black skirts, pink streaks in her hairher sense that life is a game and that the harder one works, the harder one should play, are part of a personality that seeks the big picture, and sees no reason to waste time in getting there. She moves with lightning speed, which I learned after I asked when I could come to Oxford from Chicago to visit. "Well, next weekend's good," she replied. "Once she's made her mind up she sees absolutely no reason for delaying," says Lowe. "You can't try to slow her down. You know it's quite frustrating sometimes what you have to go through, with procedures and bureaucracy. Sometimes people think Susan cannot handle too many tasks. The answer is that they can't. She can." Though

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she learned to focus her research, her life thrives on the same "scattiness" that Mellanby observed three decades earlier. "It's no good telling her she can't do something," says Lowe. "With Susan, you have to find a way so she can fit in twenty things in an hour." Standing outside her new London apartment, a perk of the Royal Institution Directorship, she stared out at the line of black taxis waiting to get to Piccadilly. She was telling Atkins about an idea. She wanted to put a bar and restaurant into the Royal Institution building. There would be a salon of science for Royal Insitution members where anyone could bump into someone who was interested in science. There were sports bars, why not a science bar? It could work, she said. Is it that a researcher stumbles onto something in her early twenties, which by incredible luck turns out to be the crucial missing link in the most sought-after diseases in her field? Or is that she is such an enthusiastic communicator that she makes investors believe she has found a critical link that most others are ignoring? It is safest to say, "perhaps a little bit of both," but that would be ducking the question. When asked if her investors will get their money back, she responded, "Maybe. That's the whole point of investment capital." The slow accretion of evidence at Synaptica suggests something at least significant is going on with acetylcholinesterase. Ironically for a thinker who flitted so much from field to field that she struck many as too scattered, her heroes are people like Dale and Florey, who stayed on a topic for years and years after what seemed to be thudding defeats in the laboratory. Greenfield has always stayed on her enzyme, but brought to it an interdisciplinary passion and entrepreneurs skill. Step by step, learning electrophysiology, and then molecular biology, collaborating with experts in genomics and animal behavior, placing tubes in rat's brains and then funneling in cholinesterase, watching their behavior and studying their brain cells after they were killed, she pushed deeper into the basic mechanics of mind. She did all this while mounting a uniquely successful public life in science, eclipsing those who scoffed at her in her early years. Perhaps it was because she ranged so widely in her media appearancestraveling the world for the BBC series in 2000, for instancethat she could stay focused on a single major thread in her own research. Like Dostoyevski's gambler, Greenfield placed her bet early and followed it through. Academic science has meant for her, paradoxically, being more practical than most researchers in the past. "She sees the consequences

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in what might initially be perceived to be an academic connection," says Atkins. "It's a part of her global vision, not only in people getting together," to attack consciousness as a whole, as a complex system, "but also for the practical consequences of her work." A typical weekend at the country home outside Oxford used to mean shutting themselves in their respective studies to write books, but for Greenfield all that has changed. "She's in the nerve-wracking mode at the moment, doing the Directorship of the RI and also the BBC series she signed up for, and the prospect of maintaining momentum at Synaptica is probably as daunting now as when the Christmas lectures were being done. More so," says Atkins. Her single biggest challenge was to find the time to stay in the laboratory. By the end of the school year in June 1999, she had resigned her tenured position at Lincoln in order to devote full time to the Royal Institution and Synaptica. Perhaps her work was not brilliant at first, but it showed the necessary quality of being inevitable in retrospect. Greenfield saw a commonsensical approach and had the novel idea of not allowing anything to keep her from pursuing it. Immediately. Of her place in this moment in the history of science, Greenfield saw a field in "desperate need of a paradigm shift. This is rather sad that people are now preoccupied with the minutiae of things and the basic premises are all rock hard, like . . . the brain region has very specific functions," she said. "It drives me nuts, because the mind is . . . a highly dynamic, changing organ, otherwise you'd always have the same consciousness." The complex-systems challenge of neuroscience, along with the explosion of popular interest in the topic, made her "perfect for her moment in history," said Sandie Lowe. Swift, rigorous, a little crazy, she brought a humanist's approach to individuality to a discipline bent on reduction and abstraction. She considered using her media stardom to push the experiments that would test her theories. When she despaired of getting the time to do her experiments, she planned to use her BBC series on the brain to conduct imaging experiments on humans to test her theory of consciousness. "I can use the program to persuade someone to let me run experiments on camera," she said. "You could manipulate different neuron assemblies and see if you could predict certain cells getting bigger." When I checked back with her a year later, she had found something more valuable in doing the series. "It is a refresher course in advanced neuroscience, because we're going into areas like vision and language that are not my area at all. But I'm revisiting and interviewing all the leading scientists in it, and that is a fantastic way of seeing the wood for the trees."

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Thinking of what there is fundamentally new to be learned in science, she mentions a favorite book, The Magus, by John Fowles. The story of a wealthy, mysterious trickster who embroils a young Englishman in a deadly game of self-discovery on a Greek island, the novel plays with issues of truth and fiction. Early in the story, the narrator awakens from a nap on the beach to find that someone has left a copy of T. S. Eliot's poem "Little Gidding" by his towel. A passage is marked: We shall not cease from exploration And the end of all our exploring Will be to arrive where we started And know the place for the first time. In the ordinary, the obscure, the seemingly known, the selfhere, the young man soon learns, is where the most frightening and important mysteries lie.

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Worlds in Profusion: Geoffrey Marcy's Planetary Astronomy 1 In 1904 the venerable George Ellery Hale founded on Mount Wilson, near Pasadena, an observatory whose work challenged astronomy's beliefs and practice. With its turn-of-the-century sixty-inch telescope and its later, 1950s vintage one-hundred-inch telescope, the forbidding mountaintop observatory epitomized the twentieth century's assault on the cosmos. Using its telescope built with gears that might have driven the Titanic, Edwin Hubble discovered the expansion of the universe on Mount Wilson in 1929. His student, the bomber-jacketed Allan Sandage, made godlike pronouncements with each new set of galaxies he photographed there. No women were allowed; its dorm was nicknamed the Monastery. Researchers wore ties to dinner (Hubble wore a tie even when up all night in the cramped metal viewing cage suspended two stories above the ground), and hierarchy dictated the seating arrangement. A rite of passage was to move up from a clothespin-clasped dinner napkin to one held in a wooden ring. The rules would have been funny if they were not taken so seriously. Phenomenally successful, pinescented Mount Wilson represented the very best of the old astronomy. By the 1980s, it also represented the most ossified. In 1982, a smallish, dark, affable postdoctoral candidate named Geoffrey Marcy was standing in the shower stall of the Monastery. He felt desperate. He had won one of the two prestigious Carnegie Postdoctoral Fellowships awarded annually at Mount Wilsonfor a project on the magnetic fields of stars' atmospheres. It was a very

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difficult, complex experiment, almost impossible, and it was going poorly. Marcy was convinced the fault lay with him. He lacked the stuff to make it in astronomy. Perhaps everyone else knew it. He paced the halls of the Carnegie Institution on Santa Barbara Street in Pasadena, from his mailbox to his office to the coffee machine, glimpsing the open offices of famous astronomers. He thought they must realize how unfit he was. He woke up every morning in pain. It had gotten so bad that a year into his two-year fellowship, when he learned that the medical plan would cover psychiatric help, he began seeing a therapist. This could not be the way for a human being to live, he thought. He was nice, athletic, smart, and successful at trying to please others. But he was going crazy. Part of the problem was the incredible difficulty of his project. Even a routine star produced almost completely chaotic magnetic fields. He had gone through agony to make little progress in understanding the complex maelstrom of star atmospheres. Perhaps, he thought in the shower, that was why he had picked the project, because it was so difficult no one could challenge him. Worse, even if he did succeed, neither he nor the world would care very much. Magnetic stars was such an arcane subtopic its few experts all tended to be a little paranoid. Soaping himself down in the tiny stall, Marcy foresaw a lifetime of incremental steps, visiting the same conferences, seeing the same faces, arguing over the same bits of jargon, specializing in ever more arcane pursuits. The idea disgusted him. Somewhere in his therapy sessions he had realized that he was always trying too hard to please others. It had ruined some relations with women. He realized that no one at Carnegie cared enough to push him to please them. Crushed under the load of research, appearances, conference presentations, they could not care less what he did. He shuddered in the yellow-green stall, looking down at the graffiti etched in the soap dish. He was selling himself short to pursue an arcane topic to please people who did not notice. He realized it was a mistake. He felt it deeply. He realized that his only hope was to find a project that captivated him. Other researchers might pursue topics simply for their career value, but not him. If it did not move him it was not in him. Usually the Ph.D. process pounded out this devotion to childlike questions; it was considered a critical flaw. But Marcy realized if he was ever going to make some contribution to the grand march of progress, he had to conjure up a project that, success or not, he truly loved. What he really loved, what had brought him onto his parents' rooftop as a child to gaze at the sky, from there to highest honors in

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astronomy at UCLA in 1976 and in graduate school, was planets. Not our familiar solar system of planets orbiting our sun; no, what he really wanted was the romantic, audacious, quixotic quest for the trillions of planets that must orbit other suns, those parallel worlds holding the possibilities of life and intelligence, the dream that drew in anyone who ever gazed at the sky. Unknown distant planets, imagined but never seen, held his soul. It wasn't the planets themselves he wanted, it was the idea that there was so much knowledge out there, so many worlds, so much richness that no one was even looking at. In the hot spray of shower water he sensed, with a flash that jolted him with fear, that if such was the case then he should pursue them. What was the point of all his education if could not go after the simplest, biggest dream of all? The roadblock was that the search for planets outside the solar system, called extra-solar planets, was considered "unsavory"the whole thing smacked of science fiction, just this side of looking for little green men. Inside the solar system, space probes in the 1970s had beamed back disappointing, barren pictures of Mars and Venus. If our solar system's best candidates looked dead, the chances of finding other solar systems seemed even deader, Textbooks barely mentioned them. The challenge was in part technical. Because they emit no light, distant extra-solar planets could not be seen except as reflected starlight, but the brilliant suns they orbited always overshadowed them. The technology would seem never to cut through this immense block. No one had a clue how to get past it. The search was strewn with bogus claims. Yet Geoff Marcy had one quality other, more pedigreed, flashier postdocs lacked: if he believed in what he was doing, he would not let go. Because he had accepted at Mount Wilson that he "was not in the fast lane, not going to invent some amazing new formula the world would marvel at." he might as well go for broke. He already considered himself a "fully fledged failure." Why not? Turning off the water, he decided. He would pursue planets orbiting other suns. He would present himself as he truly was. If he was going to be judged and rejected, at least it would be for something so extreme and moving to him personally he would gamble his shortened career on it. "It came down to something deep for Geoff," his thesis advisor Steve Vogt said. "For him this was a form of artistic expression. Like a sculpture or a painting, science was a deep expression of his soul." For such an approach, self-discovery had to precede discovery.

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2 Ever since Galileo ground his lenses and pointed his handmade telescopes at the moon, the most creative and risky of astronomical endeavors had been to seek other worlds. In a terrifying, empty cosmos, planets are the sanctuaries. The Renaissance philosopher Giordano Bruno was one of the first to speculate openly that the universe might hold infinite planets; he was burned at the stake for his ideas in 1600. Planets caused even such seminal thinkers as Johannes Kepler, the man to revolutionize our understanding of our solar system, to wax in wild speculation. When the younger Galileo wrote him that four moons orbited Jupiter, the ecstatic Kepler wrote back that they must have been placed there by God for the enjoyment of the Jovian people. Growing up during the 1960s and 1970s, in Granada Hills outside Los Angeles, Marcy hung a poster of the solar system on his bedroom ceiling. He spent every day at the park, playing baseball, football, basketball. At night, at eleven years old, he would lie in bed, staring at that poster, memorizing the names of the moons around the planets. Phobos and Deimos, Fear and Evil, spun like giant misshapen snowballs around Mars. Jupiter's moons, Ganymede and Callisto, Io and Europa, held a slight promise of life. Uranus had Miranda, Saturn Titanhe stared at them until he was cross-eyed. His childhood was otherwise pretty normal. He played the cello. He played football and loved to leap to knock down a long pass. His mother had majored in anthropology and earned a B.S., but she stayed at home with him. His father was a mechanical engineer working on jet airplane design. Both had a sort of scientific bent but they "were not particularly what you would call academic intellectuals." They emphasized schoolwork, but genuine curiosity more. When he was thirteen his parents, noting his interest in astronomy, bought him a used four-inch-diameter telescope, which he parked on the flat roof of the family home. Standing amidst the thicket of TV aerials on the other neighborhood roofs that were picking up "Lost in Space" or "The Twilight Zone," he stared and stared at the planets, watching their movement and imagining. Nothing amazed him more. Venus glowed its cordial, cool morning iridescencewaxing and waning in its motion like the moon; Mars angrily beamed orange; Jupiter swung across the ecliptic like a monarch, requiring twelve years to complete one orbit. This was as close to the sacred as he could get.

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The planet he liked looking at most was Saturn. Not only could he see its rings swooping from the flattened yellowish saucer, but he could also watch its giant moon, Titan. Titan had a nitrogen-rich atmosphere much like that of primordial Earth. Reddish brown hydrocarbons, the building blocks of life, blanketed its frozen surface, perhaps even falling as snow. Night after night he watched as Titan wound around Saturn, completing its orbit in just 16 days. ''I was amazed you could come back the next night and the night after and see this moon moving around. It was mind blowing. I kept a notebook with sketches of the positions of Titan relative to Saturn. I actually figured out the orbital period and compared it to the experts'," he said. "I was bang on." Majoring in astronomy at UCLA, he managed to hold onto that awe, enough so that, when he himself went on to teach, his students would award him with the highest evaluations. He then took his doctorate at the University of California at Santa Cruz, where he worked with tinkerer Steve Vogt on the design of instruments for his star magnetism studies. "I was in my first year as an assistant professor and Geoff was this very smart graduate student," Vogt recalls. "It was more a collaboration than a teacher-student relationship. 1 learned as much from him as he did from me." This openness from teacher to student, and relationships like the one with Vogt, marked Marcy's entire career, putting him in line to lead the new interdisciplinary astronomy that would challenge the hidebound Mount Wilson. So did his devotion to childlike questions. The university controlled a somewhat Gothic observatory built in the Diablo Mountains near the northern California coastLick Observatory. Named for an eccentric nineteenth-century mogul, James Lick, who originally wanted to build himself a pyramid in the middle of San Francisco, Lick Observatory stood on top of remote Mount Hamilton, flanked by a diner in a Quonset hut where the astronomers ate. The highest winds on Earth were recorded there according to a plaque in the cramped control room, which, with its 1950s technology, resembled more a college radio station than a professional observatory. Bobcats and mountain lions roamed the surrounding precipices. One night when it was pouring rain, Marcy stayed up talking and talking with a student named Todd Lauer. They were waiting to see if the weather cleared, in which case they would observe. About three in the morning they opened their midnight snacks provided by the dinersandwiches, chips, cookies, and an apple. Marcy began speculating about extrasolar planets. There had to be some way of detecting them, he said. How could stars harbor planets and there be no way to find them?

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Planets exert gravity on the suns they orbit. The stars wobble. You could measure the star's wobbling he said. Lauer went on to run his own institute. Marcy forgot the conversation, yielded up like a dream from his unconscious, until years later, when Lauer reminded him of it. At Mount Wilson the competition and hierarchy stifled him, and he would remember that years later. "I thought I just didn't have whatever it takes. So I thought well, maybe I shouldn't push myself to be in the fast lane." It was the 1980s, and "upwardly mobile" was the cliche among his old high-school friends. Marcy told himself he was "downwardly mobile." With his softspoken willingness to be awed, his absolute enthusiasm over the slightest blip in an experiment, he was the opposite of the all-knowing graduate from the glitzier schools. He still played the cello avidly. He felt daunted about declaring to the world he was into the ''madness of astrophysics." It did not help that in the 1980s the bottom fell out of government and university funding. Applying for teaching jobs after Carnegie he received only one offer, from San Francisco State University. An enormous city institution following an open admission policy, San Francisco State required him to teach three classes a semester, two huge lectures and one lab course. He was exhausted by dinner. With his other duties, he worked forty hours a week. A research institution might have required one or two courses a term from him. The job seemed to foreclose cuttingedge research. "The effect was dramatic," he says. He could publish maybe one paper every three or so years, instead of the three a year a full-time researcher should. For seven years he struggled in his tiny cubicle of an office on the tenth floor of cinder-block chic Thornton Hall. There was no secretary and the photocopy machine was usually broken. He had to fix the oscilloscopes before labs. He got hold of an early VAX minicomputer, and generally had to fix that too. There was no choice. He had to get out a screwdriver, pull out the back plate, pull out the boards. It was ridiculous, spending the few hours he had free to fix a computer. For seven years he could not attend the usual conferences. His work flowed opposite to the current fads, but then again it could not be shot down since he did so few presentations. His student evaluations scored among the highest in the college. His science was a form of teaching; like art, it was meant to communicate, as the great physicist Robert Wilson once said, and to connect, as the novelist E. M. Forster wrote. With the rise of computer astronomy, he could do the new intuitive science he envisioned on the cheap. He turned disadvantage to advantage, but no one, none of his later colleagues at Harvard and Berkeley, would ever know how hard it was.

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3 From his beginning planet search at Carnegie, Marcy approached the problem of searching for distant planets by using his knowledge of the complex systems of stellar measurement. Because a large planet exerts a strong gravitational pull on the star it orbits, if you take careful enough measurements of a star's motion over several weeks you should see, if it has a planet of Jupiter's size or larger, that the star wobbles a little. You could not see the planet directly because of the star's overpowering light, but you could see it indirectly by looking for tiny variations in a star's radial velocitythe speed with which it receded or approached Earth. Using a spectrometer to measure subtle changes in the wavelength of light from sun-like stars, Marcy planned to use the Doppler effect, by which light waves from a receding object lengthen, shifting them to the red end of the spectrum, to find the star wobbles and thus, he hoped, extra-solar planets. If a star swayed to and fro because of a planet's gravity, its light waves should cyclically lengthen and compress, even if by an infinitesimal amountsay 1 part per 10 million for a planet Jupiter's size. He gave up a good part of his life to the search. After teaching all day he headed home to Berkeley at six in the evening, ate a quick dinner, then worked until midnight. The next morning he awoke at seven do the whole schedule again. "Geoff was more motivated and efficient than most anyone," a Berkeley researcher, Gibor Basri said. "He amazed me." The same motivation that had Marcy practicing his cello late into the night, classical and jazz, kept him going through those grueling years. ''Things were sacrificed," he recalled of that time. "I didn't get married. Some girlfriends came and went. But it was exactly the way I wanted to run my life." His first attempts were crude. In the beginning he could only hope to detect, at best, planets with masses at least five times that of Jupiter. No theory really allowed for planets that big. "It was far fetched, but then again, I thought there was no reason planets could not be that large," he says. "Why shouldn't they?" He then had to wangle time at Lick, because it was reserved for University of California researchers, not San Francisco State teaching faculty. "I had to talk and talk with the director, and even then, because I had no formal access, I could only get the crumbs," he said. "When the sky was white with a full moon, I'd get the telescope. Two nights every six months." The ironic thing was, while everyone else was going after distant galaxies, which required pristine viewing conditions, Marcy could do

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his work with nearby stars even in fairly dense smog. It was dirty astronomy, and he felt it. When they sat for dinner in the tiny Quonset hut set high on the snowy mountain, the wind howling outside, a group of astronomers huddled together in a claustrophobic cabin, they talked about their work. When Marcy said he was looking for planets, the others looked at each other, wondering if he was joking. The idea of such giant planets seemed heretical and Marcy's approach to them impossibly complex. He needed help but his work was so loopy and isolated he could not seek a colleague to assist him. He could not even admit to searching for extra-solar planets in his grant proposals. Instead, he wrote that he was looking for brown dwarfs, stars not quite big enough to become full-fledged stars but too big to become planets. For help he turned to an undergraduate who found the idea so wild and outlandish that he could give his "heart and soul" to it. Paul Butler was a tall, thickset, outspoken, bearded student who had "the only interdisciplinary major in chemistry and physics I'd ever heard of," said Marcy. Like Marcy, Butler also grew up in the Los Angeles suburbs, building his own reflector telescope at the age of fifteen. Disheveled in his usual blue work shirt, white pants, and white sneakers, he was more of an intellectual than Marcy, avidly reading the science fiction of Robert Heinlein and "grokking" at a young age Kepler, Galileo, and Giordano Bruno. "Bruno was like the Magic Johnson of his time," Butler said. Marcy, by contrast, was a painfully slow reader who loved to linger over an author's words, drinking in the style. By seventeen, Butler was taking college physics and chemistry, and ended up taking so much chemistry that he simply took a double major. Butler met Marcy in the fall of 1985, and by the summer Marcy was putting him to work. Their dream of detecting such a small movement in a giant star a hundred light years away, on the order of the speed that one bicycles across town, required some incredible yardstick. No one had the technology to do that when they started. But in 1985 Marcy read a paper entitled "Stellar Radial Velocities," in a conference proceedings, that made his pulse race. Bruce Campbell and Gordon Walker, at the University of British Columbia, had a yardstick: hydrogen fluoride, an odorless, colorless, and deadly gas. Hydrogen fluoride absorbed certain signature wavelengths, leaving a telltale grid of black lines on a star's spectrum. Placing the gas in a vial over their detector, Campbell and Walker could compare its grid with many observed spectra to seek the shift that would give away a star's wobble. They had been at it for almost ten years in the 1980s. In retrospect, if they simply

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expanded their search, they might have been first to find a distant planet. "They were doing better than I was," Marcy said. "I thought well, I better either give up, or adopt some of their approach." Marcy and Butler were not about to mess with the highly explosive chemical, Butler's chemistry background became critical as they searched for an alternative. They spent a year travelling to libraries, speaking to worldrenowned chemists, consulting tones. Marcy was on vacation in Cameroon in Africa with a girlfriend, taking bush taxis, thinking the whole time about that gas, when Butler called. Over a crackling line Marcy heard him say, "Iodine." Iodine possessed an intricate and stable absorption pattern. The wobbles they were seeking were incredibly slight, one-thousandth of a single pixel in a detector of two thousand pixels, but the spectrum grid of iodine was accurate enough "to give them God's own spectrum" said Vogt. They worked on their computer code, designed to pull out variables like a star's twinkling, the Earth's rotation, the sun's spinning outward to the edge of the Milky Way. The code resembled somewhat the assemblers Venter used for gene sequences or, more precisely, the codes highenergy physicists used to analyze their billions of particle accelerator collisions. One spring semester in college, Marcy had written a perfect little fugue. It was one of the most joyful artistic creations of his life. Sometimes, on a few very lucky nights, writing the code felt like that too. Coupled with their increasingly subtle computer programs to pick out the variation they were looking for while blotting out the background noise, the iodine-cell approach seemed a good one, at least to them. They began taking readings at Lick Observatory. With its treacherous, winding road that closed down in winter, the remote facility was especially apt because it had specialized in measuring the radial velocities of stars since its opening in 1901. They had a terrible time at first. It was gritty work. The observatory was icy cold, open to the winter nights so that the mirror would not fog. They started with a list of stars to catch every night, then waited months or years to digest the data. If the planets they sought had orbits as long as Jupiter's, they would not know if they had anything for another twelve years! Butler fought to get their software working. The code combined a million numbers into one, simulating hundreds of physical interactions; it was difficult, frustrating, lonely. "There was no one to turn to for help, no textbook or expert," he says. Problems would take him a year, sometimes more, to solve. A million pathways led to the wrong answer with no signpost to the right one. It did not help that an optical flaw in the lens of their spectrograph caused much of the error.

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Nor did it help that they operated on a budget averaging about $30,000 a year from 1987 until 1995, much of it simply Butler's salary. It was less than science on a shoestring, it was small-team slash-andburn science for nothing. Others too began going after extra-solar planets. Teams from Harvard and Canada and elsewhere devised bizarre methods for planet detection, like interferometrythe blocking out of starlight by sequencing the rays to cancel each other out. They were making all sorts of competing claims, always disproved in the end. Marcy and Butler gave the world little reason to think their approach would work. Reporting on the project at Harvard's Center for Astrophysics in the summer of 1992, Butler talked about the complications of carrying out a full physics-based computational model of the observed spectra, along with the six hours of mainframe computer time required to analyze one ten-minute spectrum exposure. "They just laughed," he recalled. Of the four competing groups, conferees put the little San Francisco State group in "third or fourth place." Indeed their first publication announced failure. Of sixty-five stars they studied painstakingly in their first years, they found "absolutely nothing. It was quite a stunning paper in fact," Marcy recalled. "Although I think my honesty helped me gain some credibility. There were so many false detections that it was a refreshing twist to publish a paper saying we found none." Marcy still had two small critical triumphs in the early years. One was to win a NASA Innovative Research Projects Grant in 1992, funding designed for original or crazier projects that might otherwise wither. The other was in meeting Susan Kegley, a chemist who came to San Francisco while waiting to begin a tenure-track assistant professorship at Williams College. A friend working on the search for extraterrestrial intelligence introduced them. They hiked and shared a passion for Brahms. They tried duets on flute and cello, and on piano and cello. "I wasn't as good as Geoff," Kegley says. He called her his goddess. Kegley helped him persevere through bigger and bigger runs and failures. Steve Vogt also kept in touch and, when he was chosen to build the High Resolution Spectrometer for the state-of the-art telescope at the Keck Observatory, in Hawaii, he secretly created a niche to fit his former student's iodine cell. They kept on taking readings and building enormous data banks on computer disk, scanning the closest sun-like stars for a wobble. Their errors were still too large, they felt; the smallest movement they could detect was on the order of six meters per second. This would not net

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them a Jupiter. Basri advised them to process their data anyway; if there were planets several times Jupiter's size, as Marcy had speculated years earlier, they might already have detected one. Marcy went against his intuition and disagreed. Despite their lack of success, it was one of the longest periods of sustained focus they would ever know. As the power of their computers increased, they could bring less sweat and more intuition to bear on the problem. Marcy had his love, his project, his students, and his cello. He was happy. Then the bottom fell out. 4 Science competition is unlike competition in any other field. Artists, lawyers, doctors, writers, and athletesall compete with a vengeance. But they have many paintings to paint, cases to win, novels to write. In science there is only one first to make a discovery. In Geneva, Switzerland, in October 1995, a large, streamlined, government-funded team assembled by Swiss astronomer Michel Mayor discovered the first extra-solar planet, a lugubrious gas giant five times the size of Jupiter, sitting so close to the star called 51 Pegasus (or 51 Peg) for its location in the constellation Pegasus, they were practically kissing. It was strangest planet ever seen, a monstrous blast-furnace-hot ball of gas closer to its star than Mercury was to our sun. It raced around its sun in an unbelievable four days. It seemed impossible. How could it look like that and do that? How did it get there at all? Mayor and his colleague Didier Queloz announced the finding at a meeting in Florence, Italy, simultaneously submitting their paper to Nature. Word of the cataclysm spread around the world instantly by e-mail, reaching Butler and Marcy, who were already at Lick with the good weather. They raced to play the losers role of verifying the discovery. They were stunned to see exactly what Mayor had seen, a gigantic planet. When Ted Koppel interviewed them for "Nightline," Marcy played the gracious colleague. He said it was the most exciting moment of his life, confirming the existence of an extra-solar planet. Deep inside, though, they felt differently. They had been scooped. If they had processed all the data on their hard disk sooner, they might

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have been first. Well, if you can't be first, Butler thought, at least you can be the best. They had to get more computer power, fast. For any other astronomer, the announcement would have been devastating. But Marcy hung onto an inner excitement. "For all of those years we were never sure we would ever find anything." He thought of his close friend Jill Tarter, the SETI director portrayed by Jodie Foster in the movie Contact. "Her project, costing millions of dollars, expending every ounce of intellectual ability they have, might never succeed." More important, they helped save their Swiss colleagues. Incredibly, to Marcy at least, Nature had asked for revisions to the paper. This was fine, the astronomers felt, but the unconscionable condition the magazine placed on the possibility of publication was to embargo, or forbid publicity. "It wanted to have its cake and eat it too," reasoned Marcy. Years later, when Marcy would become the darling of every magazine and television program in the world, he would remember. But by being there to verify the Swiss finding, they managed to get some critical publicity out of what could have been a disaster. Still it hurt that Mayor was well funded, while they had been turned down in 1994 for mainstream National Science Foundation and NASA grants. If they had any hope they had to kick themselves into gear. To process their data, they needed lots of computers immediately. Butler spent most of the latter half of October observing 51 Peg with the little auxiliary telescope at Lick and sending out e-mail pleas for computer time. By November three research groups at Berkeley donated some, Marcy flashed a defiant smile. "Our technique is better," he said. There were going to be more planets, a flood of planets, and they were going to find the money and get them. 5 It did not take long. They already had two good candidates, and now that they knew such planets could exist, they went after them with a vengeance. One planet, orbiting a star in the constellation Virgo, was even bigger than the monstrous 51 Peg, six and a half times the size of Jupiter and about half as close to its star at its closest approach as Earth is to the sun. It was so

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big it resembled more a stillborn or brown dwarf star than a planet. More puzzling, sometimes it swung so close to its sun that it should disintegrate in a cataclysmic tide of gravity, then it slingshotted out deep into space. Such an orbit was called eccentric, and it doubled the most eccentric orbit of our solar system. It was, in short, a monster that posed deep problems for traditional ideas of how solar systems form and behave, of cosmology and chemistry. At least their second planet, orbiting 47 Ursae Majoris, looked somewhat familiar: 2.4 times the size of Jupiter, it sat out from its sun only a little farther than Mars from ours. By December 1995 they had enough data to trust their plotted orbits. Marcy had been asked to give a morning talk at the annual January meeting of the American Astronomical Society in San Antonio, Texas. They decided to announce their shattering news then. Butler felt exhilarated, but Marcy was terrified of being scooped. "We had been through it once and did not want it to go through it again," Marcy said. They spent a nervous holiday rechecking their data, monitoring e-mails and intercontinental gossip, not wanting to appear too interested in the doings of Mayor and their rival HarvardSmithsonian group. "We couldn't bear to lose our little babies we had nurtured for two years. It was very difficult," Marcy said. A rumor nevertheless got out at the conference, and the night before his talk he called Susan from Texas. "I think you better fly out here," he said. He stayed up until 1 AM working on his transparencies, going over the words he would use. He lay down to sleep. He watched the clock go to two and then three. The last time he remembered looking, the clock said 3:45 AM, and then the radio was summoning him to wake. Scheduled to speak at 8:45 AM, he had to fight through a crowd standing shoulder to shoulder down the hallways. The double doors were jammed shut by graduate students in jeans and colleagues in ties and rumpled jackets. Faces peered at himsome expectant, some smiling, some angry. People were packed outside the double doors, craning their necks. A British television crew that had been kind to their group and thus tipped off by Marcy, began rolling as he walked in. Bulbs flashed. What a change from the morning fourteen years earlier when he stood in the shower lamenting his shortcomings! In modest tones, Marcy described their findings. He felt the sweat in the small of his back, but once he began talking all his doubts vanished. He downplayed the discoveries so much that graduate students turned to each

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other, asking What's he saying? At the end his colleagues in the San Antonio auditorium stood and applauded. The guy who had doubted himself so much he took a full-time teaching job, who thought he came in second in the biggest discovery of a lifetime, felt vindicated. He was not prepared for the world reaction. "Paul and I were whisked around in limos from one TV station to another. We didn't even know which station we were being driven to. We just got in the limo and they'd take us somewhere and some moderator would ask us questions for twenty minutes. Chaos was in control." Commentators noted his collaboration with a former student, and the triumph of a small unfunded team run by a teacher. For once, it seemed, coming in second was better than coming in first. "It also helped that Geoff was an American," observed Basri. "The science media were in place to promote the story." The real story was the planets themselves, so odd and disruptive, defying the paradigms of astronomy. Prior to Marcy and Mayor, no one would have expected gas giants to have four-or five-day orbits so close to their suns. The planets suggested richly mysterious possibilities by which solar systems could form, making the universe suddenly more dynamic and creative than anyone had thought. That these weird giants circled so close to their suns suggested they had been smashed into place, because the traditional theory of a gas cloud coalescing would not put a gigantic planet beside a star. Solar systems resembled demolition derbies, with asteroids, planets, and fragments blasting each other into new orbits, spreading the molecules of life's building blocks at the same time. They showed an odd beauty, the kind that belongs to the underside of things, like the dense, potent egg smell in the air in the moment before lightning strikes. Suddenly our solar system shed its plodding logic and rut. We had evidence of its racy past: the cratered moon and Mercury showed that our solar system was once a barbaric place. Little Mars had volcanoes and valleys far larger than Earth's, and even Earth had a cataclysmic crater beneath the Caribbean Sea and Central America suggesting ancient Armageddon. Asteroids hurtled to remind us that, if not for Jupiter's beneficent gravity, Earth might have been pummeled to bits. The Marcy universe seemed chaotic, willful and creative as a child's tantrum. It betokened a revolution not only in astronomy, but in "chemistry, biology, meteorology, and geology," Marcy said on the McNeill-Lehrer News Hour. Suddenly there were many more things in heaven, as Hamlet says, "than are dreamed of in your philosophy." Space became romantic again.

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6 NASA decided that extra-solar planets were hot, and it poured money into their pursuit. Buying a large portion of viewing nights on the new, state-of-the-art Keck Telescope, NASA turned to Marcy and Butler to spearhead the search. But another disaster struck. One of the grant judges tried to have himself declared principal investigator of their project. He wanted to use their painfully constructed iodine cell himself to search for planets. Marcy and Butler fought back, with great difficulty because he was one of their judges. Eventually, they prevailed, but the stress fatigued them. They had now snagged twenty nights a year for their computer search on the world's best telescope. With celebrity, they also found corporate sponsorship. Noting that their software ran on Sun Microsystems hard drives, the corporation agreed to supply them with their best computers in exchange for appending their logo to the team's website. Never would they have to beg computer time again. Their scrappy, small-team, Silicon Valley approach to science had worked, or so it seemed. Vogt had left a space for their iodine cell in Kecks special highresolution spectrometer, nicknamed High Res, and with that they moved into an expanded search mode with an international, Internetlinked, lean network. Butler won a position at the Anglo-Australian Telescope in Australia, which gave them access to twenty nights a year on the largest telescope in the Southern Hemisphere. During the time he lived in Sydney, Butler would join Marcy at Keck in Hawaii almost monthly. In addition to observing, Hawaii provided a beautiful meeting place for plotting strategy. A new team member and returning graduate student, Debra Fischer, took over their old Lick Observatory slot. Fischer had done her undergraduate work at the University of Iowa, and then came to graduate school at San Francisco State after marrying and having three children. She was, if anything, even more rigorous and feisty and single minded than Marcy and Butler. Marcy completely overthrew the sexist, hierarchic old system he had suffered under at Mount Wilson. They ate and partied together, and he continued to host his undergraduates one night a year at his and Kegley's home. Combining telescopes, they increased their precision and power dramatically. They coordinated the search around the world by email, instantaneously. Marcy and Vogt took readings from the Keck in Waimea, sending them by Internet to Fischer at Lick in California,

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and then to Butler at the Anglo-Australian Telescope, and the combined numbers were coordinated, like the search around the world, by e-mail instantaneously. Measuring the motion of a star a hundred light years away as it waddles like a duck in a small pond, they calibrated the wobble against a fixed point. To do so, they had to take out all the motions of Earth, whose own wobble shifted its axis a few degrees every twenty thousand yearsleading to ice ages and global warming. Even the sun was not stable, because of Jupiter's pull. Using relativity theory they marked each distant star against a fixed point in the Milky Way's center. But something was lost, "the chance for sustained focus," observed Kegley. "That was critical, but now Geoff was getting media requests and queries from all over the world. He answered them all." Marcy kept a very active website; he felt it was critical to communicate his science, and even included family pictures of his coworkers. But the drain on his time defied him. They were so busy they could not take the necessary time to improve their computer programs. For some reason the program worked better at Lick than at Keck, though there should not have been a difference. Lick was home. It became a special place for Debra Fischer. She loved the peaceful routine and escape of night viewing on their telescope. "It's a time for me to get away and just focus on the important things." She found the remoteness deeply inspiring. ''Four AM gets to be a little difficult, but I love the machines. There's no 7 11, there's no gas station or anything else. It's just the Mount Hamilton diner for the staff." Apparatus in hand, they began systematically searching the four hundred or so nearest stars. They began to pull in planets, finding three more of the enormous eccentric type like 51 Peg. Then yet another cataclysm struck. In February of 1997, in a letter to Nature, Canadian researcher David Gray argued that their "wobble" was not that of a planet's gravitation at all, but of a star's pulsation. With provocative language Gray, who had written a major text on using spectrometers, built his attack on a single abnormal measurement. To many, the tone of his piece went beyond mere scientific debate; he was getting personal. But colleagues could not dismiss him. The letter threatened to derail the entire planet search. Reporters deluged Marcy with phone calls, e-mails, and continually repetitive questions. Newspaper cartoonists lampooned him. Made furious by the time he was losing, as well as by the threat to

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their funding, he and Butler fired back in a website attached to their homepage. Gray was using a spectrometer considered out of date, they said. He declined to offer his likelihood of accuracy. There was no evidence for the pulsation of stars of 51 Peg's magnitude, but Gray took one odd number, most likely due to a mistake, and built it all out of proportion. Some colleagues, noting the Sun Microsystems logo on Marcy's Web page because it provided corporate funding, felt his or Butler's rancor in responding had "gotten out hand," said one theorist. "It was bad for science." Butler, ever open with his emotions, fired back. "If somebody supports you, you acknowledge it. Did anyone get mad at Renaissance artists when they credited the Medicis for supporting their work?" Over the next several months, four published articles, including one by MIT theorist Fred Rasio, refuted different parts of Gray's claim. Then, almost a year after his article appeared, Gray published a letter of retraction in Nature. To Marcy and Butler, the year seemed to have been nearly a total loss. The added stress and delays in research pushed Marcy into taking up tennis, which he had played in high school, very ordinarily, and now discovered he loved. He began playing every day, taking lessons from a student who was a pro, and developing partnerships with friends on the court. It became important to him that his partner enjoy the match as much as he, a "complex, multilevel kind of play." The best way to go on was to work. With their methods honed and perfected, they took more and more readings. The planets poured in, four in 1997, up to a total of thirteen by mid-1998. For the first time in human history, mankind knew of more planets outside the solar system than inside. It was a tidal shift in the study of planetary astronomy, and the momentum was building. None of the other teams from bigger institutions were finding any planets at all. Some disbanded. CNN taped them at Keck. National Geographic profiled them. The New York Times ran several features on them. Marcy, Fischer, and Butler felt they had many more planets, undiscovered planets, sitting on their data disks. They simply lacked the time to process them because of all the media requests. Marcy and Butler planned an all-out assault on the four hundred closest sun-like stars, to settle once and for all just where the planets might be. What fraction of sun-like stars had giant planets? What fraction of planetary systems resembled ours? Then they faced yet another completely unexpected challenge.

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7 One day in December 1997, Marcy was checking his usual twenty or so e-mails from around the world. The romanticism of his quest and the openness of his website (it includes family pictures of many of the team, birthday and graduation snapshots), attracted queries from all sorts of people. He always tried to respond to students, no matter how late it kept him at the office. ("I'd tell him, you don't have to do every one, but he'd say, I really want to talk to them," said Kegley.) One note caught his eye. A college freshman named Kevin Apps, from the University of Sussex, England, asked if they would send him a list of their four hundred targeted sun-like stars. He wanted to "assess their value as possibly planet-bearing," with the newest data from Hipparcos, a new European satellite. He had purchased the Hipparcos CD ROM for the equivalent of $200. Marcy did not discount him out of hand, as many scientists of his stature might have. Instead he talked with Butler. Sending their proprietary list would be dangerous. "I didn't want Michel Mayor in Switzerland to know every single move I make," But something about Apps's style made him think, "I'm going to trust this kid. Why not?" It was the kind of move that had brought Butler to the search, the kind that had linked Vogt and Marcy. "I did something I was scared to do. I sent him the list. To my surprise, about two weeks later he sent back an e-mail." It changed their approach. It changed history. Kevin Apps was a muscular working-class kid who wore his sandy hair cropped and his left ear pierced with a large gold ring. He grew up in the end of a block of row houses in Crawley, near Gatwick Airport. His father was a postman. In his bedroom he kept a poster of a NASA astronaut and pictures of his favorite bands. Graduated from high school, he applied to the astronomy department in the University of London. He visited the glum, sootcovered city school buildings but, strapped for cash, decided he did not want to move away from his family and friends. Instead, he took a job as an engineer at the local Duracell factory. Thus was his life set. He worked, played soccer, and bowled in cricket, and on weekends went clubbing with his friends in town or, if they were feeling adventurous, to neighboring East Grinstead. He liked to surf. He dreamt of the big waves, the jaws of Hawaii's Big Island. He followed the news in popular astronomy magazines and then on the Web,

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which was where he learned of the careers of Marcy and Butler in 1995, much as his friends followed their favorite professional footballers. He was so avid a reader that later he proved to know more insider gossip, certainly in Europe, than Marcy himself. At night on their way home from the pubs Apps would nudge his friends, pointing up at the planets as they blinked over the taillights of passing jets. In February 1997 he was fired after Gillette bought out Duracell. Out on the dole with a severance package, he spent his time sending resumes and going to interviews for jobs he did not want. At home, he learned his mother's skin cancer had metastasized. Staying home to help his father care for her, he listened to her stories of growing up in Brighton. In April his mother died. His father moved out of the house, bequeathing it to him and his sister. Suddenly cut loose, with enough money to do what he wanted for a time, he decided he needed to get away. "I'd lost my job, and I needed to sort out what it was I wanted to do with my life," He found a travel package to Hawaii. He booked a cheap Japanese hotel near one of the most dangerous beaches on the Kona Coast. He decided he would blow his retirement money on the "holiday of a lifetime." Apps spent a month on the big island, where he surfed every day, meeting the locals and hanging out. He traveled up to tour the summit of Mauna Kea and the Keck Observatory. After he took the guided tour, he went up on his own, and even did some observing from the summit's Visitors Center. It was mid-May. He knew that Geoff Marcy and Paul Butler were up there. He looked at the twin giant domes of the telescope and wondered idly, Wouldn't it be something if someday he could be working on that? Returning in June he found some temporary work, just trying to find a job, and decided by August that finally he would go to university. He applied to Sussex so he could live at home. Before the end of first term as an astronomy major, he bought the Hipparcos CD ROM. Hipparcos was a joint European satellite cataloguing the first threedimensional map of the Galaxy. The first in a new generation of satellites, built inexpensively, making use of new electronics, remote sensors, and smart materials, it was launching a new era of observation in astronomy and had already played a key role in revisiting the question of the age of the universe. The CD ROM had just been produced for the public. Apps wondered if Marcy and Butler had had time to consult the Hipparcos data. "I thought, well, I'll ask. I was really surprised they responded. I thought, this is smashing!"

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Receiving the list via e-mail from Geoff Marcy in late November 1997, he set to work on the gargantuan pile of Hipparcos data. Night after night after finishing his homework, he filled the quiet hours in the house by "trolling" numbers. On just the third star he saw a problem. "It was not what they thought it was. It was a giant star." A giant star pulsates, meaning its signal varies too much to make the hyperaccurate readings Marcy needed. They would be wasting time and money, one the worlds best telescopes, and months of studying their data. Apps thought, "Blimey, oh Christ. They can't have realized this surely." He plowed on and found more mistakes, reaching thirty in all. "I cropped up a couple of binaries, couple more giants. I started thinking, well I have to tell them this." No one wanted them wasting Keck time, nor the years of agonizing analysis. But then again he was a little fearful of approaching them. Sitting in his cramped bedroom beneath his NASA poster, he wrote as respectfully as possible: Dear Dr. Marcy, It turns out that a large fraction [of the target stars] are not main sequence stars but subgiants and class III giants. . . . This may be a concern because . . . it probably reduces the likely number of planet detections. In San Francisco Marcy read his e-mail and laughed. "I thought, give me a break. Why did I ever e-mail this kid in the first place? And I said OK, well, let me just look at one of them. And star by star by star, he was right, every single time. Every single star he said was inappropriate, was indeed a useless star for our search. Out of four hundred stars, he had found the thirty that were no good! And we were delighted." In many ways Marcy's openness to correction reflected the same openness that had begun his fruitful collaboration with Paul Butler some fifteen years earlier. He e-mailed his pleasure with the college freshman's work. He received a response from Apps, asking, "By the way, may I suggest thirty replacement stars?" He had pulled out from the Hipparcos list some likely nearby candidates. For the first time since Galileo a complete amateur was contributing to the most expert team in extra-solar planetary search. It was unprecedented, like a Little Leaguer coming into pitch the end of Game 7 of a World Series. It never would have happened but for the trait of Geoff Marcy to work with students, going back to his old days of insecurity, his days teaching Paul Butler, to the rise of the Internet and CD ROM technology, and a whole new era in complex systems science.

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By September 1998, just nine months after he had stared up from the Visitors Center at the giant Keck telescopes, Kevin Apps was helping to set the agenda for the use of the world's best telescope. A little more than three months later, one of his suggested stars was found to hold a planet. At twenty-five suddenly he too was a media celebrity, appearing in articles from The Independent to The New York Times to The Washington Post. He appeared with the TV interviewer Johnny Vaughn on the hit morning show "The Big Breakfast." Within a few months, a well-known bread company was approaching him about doing an ad campaign. 8 Astronomer Carl Sagan has said, "In all the history of mankind, there will be only one generation that will be first to explore the solar system, one generation for which, in childhood, the planets are distant and indistinct disks moving through the night sky' and for which, in old age, the planets are places, diverse new worlds in the course of exploration." By the beginning of 1999, the leaps had been tremendous, to already knowing of some fifteen extrasolar planets, of which Marcy and Butler had found twelve. Their discovery of the fifteenth was as befuddling as the first: it was the closestjust a scant fifteen light years awayand it orbited a red dwarfs star called Gliese 876, just one-third the size of our sun. Red dwarfs are much more common stars than our sun, and much more long lived; a planet orbiting a red dwarf gives strong evidence that planets form much more readily and are even more numerous than we had long thought. "Planets appear ubiquitous, and planetary systems are extremely diverse," observed Douglas Lin of the University of California at Santa Cruz. The extra-solar planets posed huge puzzles for theorists, who wondered most of all how they had gotten into such oddball orbitshad they been pushed by cataclysmic collisions or were they infant planets surrounded by swirling clouds of dust and lethal asteroids? Lin and Japanese theorist Shigeru Ida opted for collision, picking up an obscure theory propounded by an eccentric Russian, Immanuel Velikovsky, in a 1950 book called Worlds in Collision.

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Theorists joined the argument about the implications. Marcy and Butler for their part sometimes thought about the vast new geologies and chemistries of such gas giants. They never tired of thinking about life on those planets, even the gas giants, where water might be trapped in some layer of the atmosphere. Their work made colleagues take a second look at our own neighborhood. We knew that it was once a very deadly placethe scars of the moon or Mars or Mercury attest to an unimaginable violence of collision and explosion. Our moon was likely expelled from Earth in a violent cataclysm stemming from an unbelievable collision. But on a vaster scale, it seemed that our solar system "may be a very rare event," says Lin. "We are safe, but just safe." Following on the quest for extra-solar planets, a whole new generation of NASA probes, built on the principles of better, cheaper, faster that Marcy pioneered, are poised to open a new era of extrasolar planetary exploration. The Space Interferometry Mission (SIM) will use complex wave-interference sensors called, aptly, interferometers, to block out starlight and allow planets to be seen in silhouette, while the Terrestial Planet Finder (TPF) will take "family portraits" of planet systems and atmospheres. "The first blue Earth-like planet we'll be able to see in about a dozen years," predicted NASA's Dan Goldin. "When I see that, I will weep." When Mount Wilson was founded in 1904, it opened not only a new astronomy, but a new way of doing astronomy. Geoff Marcy's personal crisis as a young researcher on Mount Wilson led not only to a new astronomyof weird new theories of planet formationbut also to a new way of doing astronomy. It was, first of all, an astronomy of nice people working on interdisciplinary teams. It was also cheap astronomy, much as the Mars Pathfinder and Explorer showed the world how probes could unlock the universe using basic video and electronic and computer programs. It was a team effort, absent Mount Wilson's old rigid social order. Kevin Apps and Butler and Debra Fischer can attest to that. Apps speculated that the reason Marcy was finding so many planets while the better-funded Swiss astronomers Mayor and Queloz remained stuck at one was that Marcy, quite simply, was nicer to people below him on the professional scale. Marcy used to coach Little League baseball, even though he had no children. "I used to ask the boys, What position do you want to play?" he said. "The other coach thought I was crazy." How was it that a relatively obscure teacher forged the method of finding distant planets? How is it that much better funded teams found many fewer? In the end, it was the go-for-it panic of a day in

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the shower, coupled with incredible drive to keep doing research every night after being exhausted from teaching, and a good deal of luck. At the American Association for the Advancement of Science meeting in 1999 in Anaheim, "uncle" Allan Sandage, father of twentieth-century astronomy, approached Paul Butler. "I saw you on TV," he said. "I just wanted to tell you what you're doing is great." Butler demurred. A Harvard University Press editor pushed up to him. "I want you to write a book," he said. "Come stop by when you're in Cambridge. We're right across the street from the CFA.'' It would have been a moment to relish, but time was short. Butler had to race out of his conference to Cambridge, and from there to New York. They were working on something bigger. Within a few months, they announced even more astonishing news. They had found the first extra-solar system with multiple planets, around u Andromedae, a sunlike star some forty-four light years away. This discovery, announced jointly with their former nemesis, the Harvard-Smithsonian Center for Astrophysics, suggested that "our Milky Way is teeming with planetary systems," Debra Fischer said on the front page of The New York Times. The momentum kept building, even as Marcy left San Francisco State for a position at the University of California at Berkeley. In November 1999 came two more important announcements. One was the first direct observation of an extra-solar planet, in the constellation Pegasus, as it dimmed a star's light by passing in front of it. The other was the announcement of six more planets around other stars, bringing the total number of extra-solar planets to a whopping twenty-eight. Announced by Steve Vogt (one of the planets had been described in a paper by astronomer Nuna Linn, of the Swiss team), five of the new planets lay in the habitable zones around their starswhere liquid water and, possibly, life could exist, most likely on the planets' moons. Still they pressed on. Marcy and Butler are committed to finding Saturn analogues in the next few years, and to being the first ones to find an Earth-type planet. Geoff Marcy could not have done it alone. Paul Butler could not have done it alone. Only together could they have made the approach work. But what of the worlds that produced such theories? "Sometimes in the middle of night we just look at each other and say, I can't believe we're doing this," said Vogt.

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Dangerous Liaison: Polly Matzinger's Evolutionary Immunology I say Live, Live, because of the sun the dream, the excitable gift Anne Sexton, Live 1 When Polly Matzinger thought of the theory that would challenge nearly a century of immunology doctrine, she was taking a bath. She was thinking about a problem, and she did her best thinking in the bath. She reviewed papers for the journals Science and Nature in the bath, as well as for some of the journals in her field. While soaking in the steaming water, she wrote the papers and presentations that stirred up a tempest among her colleagues. The warmth of the water, smell of skin oil, and the ritual of settling in made her feel still and focused and calm. What I needed was stillness and imagination, Einstein said in answer to the question about how he uncovered the mystery of relativity. Imagination, he added, is more important than knowledge. Lithe, small, short-haired, Matzinger was a laboratory chief at the National Institutes of Health in Bethesda, Maryland, in 1991. She had trained border collies for sheep-dog competitions around the country. She had entered science later in life than most of her colleagues and approached it from a different angle. She wrote syntheses

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and summaries. She spoke frequently to nonscientists. She did not like technology and computers. And she did not like conventional wisdom. At the time of Matzinger's bath in 1993, some experts were predicting that molecular immunology was about to break through to a new era of unimagined longevity, when manmade hearts, livers, arms, and legs would extend life almost without limit. The breakthrough would be supported by "a remarkable convergence of basic research in some once-disparate specialties," according to science writer Boyce Rensburger, including molecular and evolutionary biology and gene therapy. "The immortality of the single-celled organism is in us," Rensburger wrote, a call echoed in articles and on television. The trouble was, the human body is not nearly as easy to choreograph as the visionaries claimed. The primary block is the immune system itselfthe many cells that protect us from disease and death every day. Sometimes the immune system turns against the bodyin autoimmune diseases like multiple sclerosis, rheumatoid arthritis, Type I diabetes, and lupus. Other times it rejects transplants of matched organs unless they are accompanied by massive doses of immunesuppressing drugs that weaken the very person they are meant to help. More perplexing, the immune system frequently does not recognize cancerous tumors until it is too late. Despite all the possibilities of a new era in medicine, immunology's byzantine challenge made talk of immortality a bit premature. In 1993 most immunologists were applying the techniques of cell biology, computer analysis, gene and bacterial cloning, and basic artificial intelligence to the questions of what made the body attack infection and why. When a foreign agenta virus, a bacterium, or a transplanted liverenters the body, it was known to be set upon by special blood cells that arise in the bone marrow, which gobble up the invaders. Their theory stated that, shortly after infancy, the body learns to accept what it recognizes as the self and attack elements it recognizes as nonself. Proposed in the early 1940s by Macfarlane Burnet, the self/nonself model was confirmed in the cataclysm of World War II by an urbane British doctor of Arabic descent, Peter Medawar, who studied the rejection of skin grafts. Working with severely wounded veterans, Medawar watched with frustration as the body's own immune system battled the grafts and prostheses meant to help the victim. After the war ended, Medawar's experiments with inbred mice seemed to prove the self/nonself model. For their work, he and Burnet shared a Nobel Prize in 1960. In the years thereafter, researchers sought to grasp and manipulate at a molecular level the complicated signals and countersignals

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activating and running the immune system. However, as the studies became more rigorous, the picture became cloudier. In some cases the body would not attack what appeared to be nonself, as with cancer tumors, and in other cases it would attack the self, as in autoimmune disease. What exactly triggers the immune cells, and when does it happen, and why? Those questions needed to be answered before researchers could begin to understand how the immune system could be turned on or off, They were accepted as major challenges of late twentieth-century immunology, but they were not what Polly Matzinger was thinking about in her bath. It was instead clear to her, and a few others, that the self/nonself theory was not explaining a great deal that went on in the laboratory and in life. Unlike her colleagues, who tinkered here and there at the edges of the model, Matzinger felt that an entirely new model was vitally needed, and the place to look was not only in the databut in the perception of researchers themselves. The stakes were enormous. The riddle of exactly how the immune system worked occupied hundreds of laboratories around the world spending billions of dollars; it was big business. The world, rocked by the first heart transplants, had then seen the immune system unwork the miracles of surgeons. It had to be unlocked. If it could be, anything was possible. Tissue engineering, which already helped athletes, offered the potential of one day replacing our livers, lungs, and hearts with artificial organs, promising to extend our lives up to two centuries or more. As with the genome, however, to reach such a vision immunologists needed the bigger picture, the entire system, whole. Immunology was holistic, complex systems, interdisciplinary science of the most daunting kind, and it made a giant roadblock in front of medicine's new millennium. "We saw the future," said one researcher, "but no one knew how to make it happen." As chief of the section on T-Cell Memory and Tolerance of the National Institutes of Health, Matzinger joined in on the debates, stewing all the while about a deeper, more fundamental problem she saw in the entire model. Self/nonself could not explain so many basic thingslike why a mother did not reject her lactating breast, or why a teenager's body did not reject itself during puberty. The body was always changing, often radically. If human puberty seems tough, she told her students, what about a frog's? What kept a tadpole's immune system from recognizing its growing legs or its new red blood cells as nonself? What bothered her most was that few of her colleagues even conceded this illogic. They thought they had the answers. Goaded by a young physician, Ephraim Fuchs, whose brother had died of cancer,

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she sought a deeper logic to the immune system. They read avidly from authors on the creativity of science like Arthur Koestler, Karl Popper, and Thomas Kuhn, discussing the overarching emperor-with-no-clothes problem in their field. They argued about what kind of an immune system would make sense if designed by evolution. Attractive, argumentative, and smart, Matzinger prided herself on challenging commonly accepted data if it contradicted the philosophy of good ideas. Some said Matzinger did too much philosophizing and too little experimenting and publishing in professional journals. Others said she rekindled the most time-honored approach to science, synthesizing numerous studies into new ideas. She was verbal and smart and different, and she got attentionfirst in a BBC series, then in women's magazine articles, then in keynote speaker engagements at major science conferences in Europe and South and North America. What she did with that attention inflamed some of her colleagues. An adept actress, she flaunted many of her field's traditions. She once named her dog as a coauthor on a journal paper. Her curriculum vitae listed jobsyears of playing jazz bass and piano, waitressing, carpentering, serving in the Church of Scientologythat few other scientists would include. She even listed her former job as a Playboy Bunny at the top of the document. She drove with a bumper sticker that read "Commit Random Acts of Kindness" while amassing $500 a year in parking tickets. She admitted to "having a brain like a sieve" but challenged speakers' inconsistencies doggedly at conferences. She played the piano and sang with a folk group, wore leggings and boots around the halls of the Bethesda complex. Above all, she did not worship the prophets who promised a new era in immunology, not without reevaluating what she saw as its faulty conceptual basis. When she leapt out of that bath in 1993, dripping, "absolutely naked, running through my house," and screaming, she had come up with a new model that threatened to turn her field, and the future of research, on its head. If true, her idea could transform immunology. But was it true? Was she for real? On that point, even some of her closest colleagues could become apoplectic. "People still will not give her any credit," observed her NIH Director Ron Schwartz. "Polly is so refreshingly controversial," said Case Western Reserve University's Paul Lehmann. "She's just what a scientist should benot by the book, not into systems and structures, but sometimes she has to pay a price for it.'' At the beginning, she had little of the experimental data one would expect, yet she managed to motivate dozens of labs to attempt a new immunology.

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Was she a harbinger of a new kind of interdisciplinary science, or the worst example of old-fashioned dilettantism? The complaints about her resembled those about Craig Venter or Susan Greenfield, But Matzinger took it to a new level. "Polly," Johns Hopkins University oncology professor Drew Pardoll once observed to the magazine Elle, "is a very dangerous woman." 2 History often works by accident and mistake. For the seeds of revolutions look into the wings of obscure events and trivial coincidence. In 1947, the same year Peter Medawar tested the self/ nonself theory, Polly Celine Eveline Matzinger was born on July 21 in La Seyne, France, to a Dutch resistance fighter and a French former nun. Her father, who had been sent to Dachau for assisting Jews, now worked odd jobs to support his painting and his wife's pottery design. After moving to Amsterdam, the family made it to the United States, where Matzinger and her younger sister were not allowed into a Long Island elementary school because they did not speak English. Her father then took the family west, settling in Hollywood because Los Angeles County would allow his children to attend school. Matzinger and her sister were placed back a year because of their language. Bored and lonely, she later found solace in her brother's beagle, named Trixie. At age eleven, Matzinger saved up dollars earned from sweeping a candle shop to bring Trixie on a rope to a training school. "I told them I would pay them a dollar a week. They lent me a leash and a collar and treated me like an adult." By junior high, her father had moved the family to Watts, where she learned music from the first teacher to take her seriously. For her senior year of high school, the family moved again, to Laguna Beach, where, feeling isolated once again, Matzinger told the guidance counselor she wanted to quit. She skipped classes to attend a nearby community college, where she made A's in some of the classes she attended. She also failed several that did not inspire her. Her senior-class yearbook listed her as "Most Likely Not To Succeed."

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She kept up her dog training and music and did well with them, but little else. She attended junior college in music, and the University of California at Irvine, but quit before graduating. She decided, she said, "that any job was boring and so I would take only those jobs that would allow me to do what I wanted during the day." In her twenties she cleaned bricks for two cents a brick. She ironed shirts at ten cents a shirt. Her favorite job was dog trainer, which she loved for its "unspoken communication, like a marriage," She had a rare ability to listen to the animals she worked with, letting them tell her how to teach them. The rest of her family was artistic, but she felt like a talentless dabbler. After stints as a waitress and a carpenter, punctuated by gigs playing jazz bass for club dates (she admired Charles Mingus), she moved to Boulder where she became a bumper pool Bunny at the Denver Playboy Club. "It was a great job,'' she says. She enjoyed talking to people. She could listen intently, making members think they were the only one in the room, as she did in telling me the story of how she ended up driving a police squad car, in the middle of a snowy night, in her Bunny outfit. One winter night her beat-up Volkswagen blew a tire, so she hitchhiked to work in the icy cold along Interstate 95. Arriving late, she ran into a police detective named Duffy, who was waiting to give her a lesson in bumper pool. When she explained that her car was broken down on the highway, he offered to fix it. The bell-bottomed detective returned after a few hours to say her car was ready. When she thanked him effusively he paused. "Well, you could do me a favor," he said. He wanted to use her car to go on surveillance at a "drug party." She hardly wanted to help a narc, but she felt she owed him. He met her when she got off at three in the morning. The wind whipped up cinders and sleet. She wrapped her tattered faux leopard coat around her. He showed her how to run the squad car's lights and siren. She drove it almost all the way home, until a Boulder policeman pulled her over. "Is that, " he asked, "your car?" At the police station they checked their computer and found there was no Sergeant Duffy. "There had been a Private Duffy in the tiny Green Mountain Falls police force," she recalled, "but he had been fired two years before." Private Duffy had absconded with a squad car. When she heard that, she thought she had lost her Volkswagen. But the next day he returned it, still insisting he was a detective. From Boulder, Matzinger made her way to Davis, California, eventually waitressing at a bar called Mr. B's. She liked chatting with two regular customers, one of whom was the University of California

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animal behaviorist Robert Schwab. If there was one thing she understood, it was animal behavior, When she overheard them talking about deceptive mimicry, she chimed in that she never understood why a raccoon did not impersonate a skunk to scare off predators. Schwab looked up. "What," he asked, "made you think of that?" Schwab began talking to her regularly, bringing in articles for her from Science, Nature, and Scientific American. He encouraged her to finish her undergraduate degree and pursue science as a career. He even helped her fill out the applications. "He gave me my life," she recalled in a BBC documentary. "And I never thanked him. When I published the danger model I wanted to send it to him, but I didn't think it was good enough. I wanted some more time with it." A few weeks later, he was dead. 3 In 1954 Peter Medawar's proof of the self/nonself theory was both elegant and simple. Medawar showed that, while adult mice reject foreign skin grafts from other adult mice, a newborn mouse will eventually accept such grafts. He concluded that the body's immune system will accept as "self" any cells it encounters early in life, while rejecting as "nonself" any such cells encountered later in life. His model seemed so clear and inevitable, his prose so reasonable, as to be unassailable. Medawar went on to something of a second career writing about the sociology of scientific inquiry, penning books like Advice to a Young Scientist and The Art of the Soluble. At the University of California in San Diego, Polly Matzinger began by studying the sex lives of fruit flies, but under the pressure of answering an oral exam question, she had her first creative scientific idea. "It was in immunology," she recalled. "When you come from a family of artists and you're not creative, and you find a field you can be creative in, you switch." Under the mentorship of two leading immunologists, Mel Cohn and Richard Dutton, she put to use her ability to communicate with animals, to listen, argue, and synthesize in the study of the immune system.

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From the beginning as a graduate student, Polly Matzinger had felt uncomfortable with the self/nonself theory. Even Medawar had seen as early as 1954 that it could not explain something as simple as why a pregnant woman's immune system did not attack her own fetus. The fetus was foreign; why did the body's immune cells not react? Medawar held that there must be some anomaly in female biology, not in his theory. Matzinger called that a typically male response. Self/nonself had other, bigger problems. It did not explain phenomena like autoimmune disease, when the body turns on itself, or cancer, when the body fails to attack foreign tumors. It did not explain how we develop new tolerances as we grow older. If the body was always changing, it did not make sense that its immune system, after infancy, always remained the same. In the 1970s the stakes in immunology became suddenly enormous. Those were the heady years of the first heart transplants. The accomplishments dazzled the world but then often ended in an ignominious death as the body itself slowly rejected the lifesaving organ, or accepted it only with massive drug doses to suppress the immune system. It seemed a cruel anomaly: the patient's body assaulted the organ that the surgeon had so brilliantly implanted to save it. The trouble appeared to be that each person's immune system was slightly different. We each evolve different immunities picked up from the different illnesses we get, adding to the different sets of parental immunities we inherit. The heart or liver from an organ donor, it was reasoned, could not be recognized as self by the patient's own immune system because its genes were different from the patient's. The patient's system then attacked. In the following years, several advances in molecular biology began making it possible to understand what was going on down to the level of the molecules in the cell, unmasking how the body recognized nonself in the immunological model. The mysteries of cell recognition, signaling, life, and death, began to open. It was known already that the most important immune system signaler is the helper T lymphocyte, a white blood cell that stimulates other cells to action. A T cell recognizes an invader by its antigens, molecules presented on the foreign cells' surface. When it does so, the T cell starts to proliferate and causes an army of B cells (producers of antibodies among other things) to proliferate, too. How did all this happen? Not as simply as Medawar imagined, it was turning out. Mel Cohn at the Salk Institute, in La Jolla, California, was a leader of the research into the signals of the immune system. Across the ocean Australian researcher Kevin Lafferty, who would become a

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Matzinger supporter, was studying the complex mechanisms of antigen-presenting cells, which first encounter, engulf, and digest an alien cell or a virus, then activate other immune cells by "presenting" the pieces to them. The question was, what triggered the antigen-presenting cells themselves? In 1976 Cohn invited Matzinger to go in his place to the most important world conference on immunology, held every decade or so at the august Cold Spring Harbor Laboratory run by James Watson. At the end of the meeting she met a young, rumpled Yale researcher named Charles Janeway. She became good friends with Janeway, who came from an august family in immunology. In 1917 Janeway's grandfather Theodore was called on by the U.S. Army to diagnose doughboys who were falling ill. He lived long enough to uncover pneumonia, and then died from it himself. In the 1930s his father, Charles senior, had been a pioneer in the field. The younger Janeway would later cowrite the definitive text in immunobiology and preside over the national immunological association. He was traditional science, she an upstart, and she wondered if one day she would ever be invited to speak at a conference as important as Cold Spring Harbor. In her forays into professional meetings, being attractive was "an advantage and disadvantage." With her reputation as a former Bunny, she could always get senior scientists to talk with her, she said. It was just hard to get them to talk science. Inflamed by the meeting, though, she began to take off. Before she earned her doctorate she was to publish or coauthor four papers in major journals, all attacking the question of what mechanism switched on the immune system. She was proposing a model that seemed at first unlikely, but then turned out to be exactly correct. It was "an important, creative argument early in her career," observed Ron Schwartz of the NIH. But for her fourth paper, she committed an act that might have doomed her career. Refusing to write in the usual scientific passive voice ("steps were taken") and too insecure to write in the first person ("I took the steps"), she instead invented as coauthor her afghan, Galadriel Mirkwood, so she could write "we". The Journal of Experimental Immunology, which published the article by Matzinger and Mirkwood, was incensed when it learned of her deception. It banned her from its pages. Being such a passionate speaker, an actress, and a debater who deliberately tweaked boundaries all put her in the same dual-edged position. She was in immunology but not of it, "within and without" like F. Scott Fitzgerald's Nick Carraway.

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4 In 1979 she returned to Europe for her postdoctoral work. First Matzinger went to Cambridge, where she was an NIH overseas fellow working with immunologist Herman Waldmann. She then took a research position at the Basel Institute for Immunology. Professionally it seemed a good match, but personally it was a disaster. There was no place in Swiss society for an independent single woman, certainly not one who advertised herself as a former Playboy Bunny, played jazz, drank and talked freely, and rode a BMW motorcycle. Matzinger continued to demonstrate that she could perform seminal experiments, publishing papers in Nature that examined the role of the dendritic cell and thymus in immune response. Dendritic cells, found in lymph nodes, the spleen, and, in low levels, in the blood, are particularly active in stimulating T cells. She did pioneering work on their function. Still "Polly didn't do a lot of reading in the literature. She tends to be much more of an intuitive person. She did not do a lot of writing up," her later NIH section supervisor Ron Schwartz commented. She was more a creature of meetings and discussions. Once, she kept Schwartz up until 4 AM arguing the night before he was to make a major presentation. Hers was almost an improvisational form of science research, like jazz. "At some point you realized you just weren't going to win," Schwartz said, "so you gave up." In her last year in Switzerland, her beloveed afghan died. She was so depressed she drove her motorcycle well past midnight, drunk, up and down the cobbled sidestreets. That was when she heard from Schwartz, who had just become a section chief at the National Institute of Health in Cellular and Molecular Immunology. He could hire two researchers. Schwartz invited Matzinger to give a seminar in 1988, the same year she was asked to speak at the very Cold Spring Harbor Conference she had aspired to more than ten years before. Schwartz wanted someone to provide "an intellectual spark" and who could mentor younger scientists. She galvanized the audience. She would always be a favorite with postdocs, attracting young people from as far away as Turkey and India, especially women. He offered her a choice of two positions: one lower paying with the option of tenure, the other higher paying but riskierit did not offer tenure. Matzinger was not sure she wanted to return to a "country that didn't know it lives in the world," but it was a good time to come. The National Institutes of Health would in a few years undergo deep

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changes under the leadership of Nobel Prize-winner Harold Varmus. Since 1937, when Congress founded the largest and best-funded of the NIH Institutes, the National Cancer Institute, the NIH had epitomized the paradigm of huge government-funded bureaucratic research. Franklin Roosevelt called it a war effort to eradicate disease. Under Varmus, the NIH instead committed to creative, individual, big-picture, risk-taking basic science. Matzinger chose the second, riskier position. "I figured if I can't do something in four years to make somebody want me, I belong in another field." Needing to earn tenure, she had to sit and put her thoughts on paper more regularly. She needed to do experiments. On the first floor of sprawling Building 4 in Bethesda, her team worked side by side with Schwartz'sgiving plenty of opportunity to share ideas in the open hall. She liked to write philosophical questions in magic marker on a white board in the lab tea room, just as she wrote herself notes on a blackboard in her kitchen at home. A young postdoc working with Schwartz, on a leave from his training in clinical medicine, began writing down answers. Born in 1960, the dark, intense Washington-raised Ephraim Fuchs learned at the age of fourteen that his father was suffering from colon cancer. At fifteen he learned that his talented older brother had brain cancer. After his brother's death, Fuchs decided he would become the person to cure cancer. Coming to NIH in 1988, Fuchs was still fairly new to the field. Schwartz put him to work figuring out how to create tolerance for transplant antigens. He was "flailing around and not getting very far." The molecular biological revolution was sweeping labs around the country, and Schwartz's interests veered more toward cellular systems than to the big-picture questions involved in curing diseases that Fuchs yearned to pursue. When the cloning of genes for T-cell receptors became possible, the problems of molecular immunology seemed finally within researchers' grasp. Fuchs was having trouble and found in Matzinger an open door and fellow spirit. "With others, you had to make an appointment just to see them," he recalled. "Polly was more of a classical cellular immunologist, so when I had problems with my experiments it was easier to consult her." Matzinger's more free-wheeling approach inspired and, sometimes, bothered him. "What's striking is that Polly works from a priori principles. She starts out by saying, if I were a God designing the immune system, how would I design it?" This philosophical, almost Aristotelian approach ran counter to the work of most other labs in the field. "Many people just generate as much data as possible and try

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to extract information from the data," Fuchs said. He and Matzinger talked and talked about the problems in their field and about the nature of science in general. They read Thomas Kuhn on the paradigms of scientific disciplines, and Arthur Koestler on creativity. They read and then argued about Karl Popper, the historian at the London School of Economics who took up such issues as whether the universe is ultimately open or closed, free or predetermined. "Ephraim was a discussive type of guy," Matzinger recalls. Their metaphysical discussions opposed the big technological approach of most government science. It was rare at any lab, at any time, and they needed to bolster each other for their assault on immunological doctrine. From the start, it was Fuchs who challenged the self/nonself theory. Thinking about cancer, he saw immediately that the body did not behave the way the theory would predict. Tumors should have been assaulted because it was clear they had antigens on them that were foreign. But researchers were spending years and millions of dollars trying to get the immune system to work against them, to no avail. For a while Matzinger played the older, wiser "grandmotherly" role, in her words, trying to explain how the discipline worked, but Fuchs would not let go. Self/nonself, he argued, was philosophically and physically impossible. "Was it Heraclitus who said you can't step into the same river twice?" he said. "The fact is the body is always changing. Tumors occur all the time, as do bodily changes like puberty, and mutations, and the immune system doesn't attack." Fuchs had read the physicist Richard Feynman, who described how, when a scientist proposes a breakthrough, he had to have the courage to suggest that maybe the previous findings were, well, wrong. Gradually Matzinger stopped talking and just listened. Perhaps the previous data were flawed. "Polly, one thing I have to give her a lot of credit for is she was able to challenge some of the icons of immunology and say, well their reasoning had to have been wrong." Around the world a few other researchers kept finding problems with the prevailing model, and strangely promising results that contradicted it. In Australia's John Curtin School of Medical Research, for instance, cancer researcher Kevin Lafferty found that an organ cultured in high oxygen is not rejected when it is transplanted because the organ's dendritic cells died off, which was unexplained by the self/ nonself model. Others, like Janeway, were stimulating the immune system to act against autoimmune diseases by combining bacteria with diseased cells. But it was one thing to suggest that a prevailing theory required modification, quite another to propose a replacement. If not nonself, then what triggered the immune system to attack?

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Matzinger got Fuchs to read Richard Dawkins, the Oxford animal researcher who had extended Darwin's theory of evolution into many new fields. He first coined the term "meme" for a cultural riff that gets passed around much like a successful gene. To Dawkins, and to his avid reader Matzinger, every aspect of life evolved to perpetuate the genes of the species, "Once you start reading Darwin," Fuchs said, "there's no going back." But the self/nonself theory seemed terribly inefficient in light of natural selection. It seemed to prevent the human immune system from evolving to pick up immunities to some agents. What use was an immune system that could not adopt new resistances? They spent months thinking and arguing about it. Matzinger sat on her cottage's back patio, working at her laptop, absently tossing the ball to her sheep dogs. She was still doing her other research on antigens and T-cell memory; in fact she was publishing at a new rate of two or three articles a year. But she kept thinking about the big picture. They decided that it was most likely, in an evolutionary world, that an immune system wired to prevent danger would be more sensitive than one turned against everything foreign. The trouble was, what defined danger to the immune system? "Danger" was just a metaphor. It sounded like a novel or movie plot device, not a scientific theory. At this point, Matzinger stepped into her bath. As she watched the bubbles pop, she thought about the two different kinds of cell death molecular researchers were uncoveringone programmed and healthy, called apoptosis, the other sudden and unexpected, called necrosis. In programmed cell death the cell's contents remained inside the cell wall. In sudden death, the contents spilled out. Those contents, it dawned on her as she watched the soap bubbles pop, could signal danger. She leapt from her bath, naked, dripping, racing through the house, her thick long hair tangled and wet. That was it! The immune system responded to danger signaled by the sudden death of cells. That was why transplanted organs were rejectedthe surgery caused severe trauma, killing many cells. That was why a mother did not reject her fetus. That was why tumors did not trigger a responsethere was no necrosis when they began to grow. "The reason I didn't see it was, I was really blinkered," Lafferty later recalled in a BBC documentary. "Everyone has to realize that we're confined by our conceptual framework all the time, even though we don't know it." It was so simple. What would be the most useful stimulus in evolution for an organism's survival? Danger, signaled by death of cells. Though she was excited, and Fuchs was too when she told him,

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the idea was no Archimedes-class revelation. Lots of people have ideas. She needed a triggering mechanism to get herself out of the realm of metaphor and into the real world. She suspected the signaler was the dendritic cell, whose functions she had been exploring, but she did not know how it distinguished between danger and safety. One Saturday afternoon Matzinger was out in a Maryland farm field, watching her border collie herding sheep. At one point the dog shot off to protect the bleating sheep. There was nothing there. A sudden sound or wisp of wind had scared the sheep. She noticed the dog responded not to a menacing animal, but to signals from the frightened sheep. Her mind worked. The bleating, she realized, signaled danger. In the body, perhaps the dendritic cell goes into action not because of an invading organism, but because of the distress signal from necrosis of its own cells. The bleating was the sudden spilling out of the cell's contents. Now the theory began to take shape. Fuchs had been talking about the idea with her for months, but it needed rigor and depth. It had to be airtight enough to be what Karl Popper called "falsifiable"that it could be supported or disproved by experiment. Some of what she was saying had already been proposed by Charles Janeway in a creative paper titled: "Approaching the Asymptote? Evolution and Revolution in Immunology." He had given that talk at the 1989 Cold Spring Harbor conference, where she also spoke. Janeway had synthesized the latest findings to suggest that the body's immune system responded not just to nonself but to patterns in antigens presented on invading cells. Matzinger adopted what Janeway said and, as she liked to recall in lectures, "took one more small stepand that step dropped me off a cliff." She broke entirely with the old model. "Hers was a profoundly deeper idea than Janeway's," said Ron Schwartz. For once her sweeping, philosophical approach might beat out the more precise voice of traditional science. ''Their ideas were similar," said Case Western Reserve University's Paul Lehmann, who later tested their models, "but Polly was more cautious and philosophical. Janeway was plain wrong, because in the absence of bacterial products you do get immune response. Polly may still very well be right." Granted tenure in 1993 and promoted to section head, Matzinger built the confidence to put her ideas to the world. But she needed a forum. In 1994 the NIH researcher William Paul asked Matzinger to write the chapter on immunology for his annual review. It was a nice recognition of her growing status, though more a review assignment than a creative one. Matzinger turned it into her big chance: to write an original workmuch as Carl Woese would do later with his

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microorganisms. Night after night she reviewed the latest findings from around the world, synthesizing and adapting them to what she snappily titled the "danger theory." She had not done any experiments yet, but the whole thing fit so well with what others were uncovering. This was why the body did not attack cancer tumors; the cells did not die until the cancer had advanced and metastasized. A mother's immune system did not attack her fetus because fetal cells do not normally die by necrosis; the same went for a tadpole turning into a frog. The seemingly mundane job of pulling together the latest news unleashed the rebellious part of her. With the same flair for the dramatic that made her lectures so popular (she gave nicknames like "the schlepper" to the body's major histocompatibility complex), that enthralled her audience with tales of mysterious police detectives who were not what they appeared to be, she dropped her bomb in the most innocuous place possible, the Annual Review of Immunology. She contacted Fuchs to show him a draft of the paper and invite him to be the coauthor. At first her younger collaborator was angry. "I had been discussing these ideas with her for months and then she had gone and written them up. And she put things in the paper I did not agree with. But I have to admit she pulled it together and explored the implications much more throughly than I had." She submitted the article with the title, "Tolerance, Danger, and the Extended Family." And then she waited for the explosion. 5 New ideas can be accepted, discussed, rejected, or modified. Or they can be ignored, either because they are crank ideas or because the field lacks the vocabulary for discussing them. Matzinger and Fuchs were met at first by silence. According to Matzinger, researchers under thirty, especially those from outside the field, liked it but could not go out on a limb. Those over fifty, especially those in the field, mostly disagreed. Those in between, the critical audience who might listen and act on her ideas, mostly ignored it. Their silence was worse than disagreement. It was to her a passive derision. She was a leading researcher who had been asked to write the round-up. It deserved some kind of reaction.

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The lack of reaction may have come partly from the fact that others were on a similar track. Indeed, Janeway was quietly furious, both with the idea and the way she went about presenting it as her own. "I have a personal grudge with her because we presented the whole thing first. Basically, what we call innate immunity she calls danger. We've done the experiments, we've got evidence. What she's saving is that anything that gives rise to an immune response is danger and that anything that doesn't by definition is not dangerous. And that seems to me to be a circular argument." She countered that her theory deeply extended Janeway's findings, which could not account for the rejection of transplanted organs. But in one respect Janeway was correct. She needed data, She needed to show that the sentry would be the dendritic cells. She needed to do an experiment. In 1996, in the journal Science, Matzinger reported what she thought was one of the needed experiments. The article, coauthored with Fuchs (who had begun the experiment in 1990, before leaving the NIH in 1991) and her technical assistant John Paul Ridge, and titled "Neonatal Tolerance Revisited: Turning on Newborn T Cells with Dendritic Cells," redid the famed Medawar experiment. This time they injected infant mice with foreign dendritic cells that had been "activated" to trigger a reaction. If Medawar was right, that all cells in a newborn mouse were tagged as "self," then there should be no immune response. If Matzinger and Fuchs were right, the cells should be rejected. The cells were rejected. This second time she proposed the danger theory, Matzinger recalled, "the shit hit the fan." Business Week said she was "standing the immune-system theory on its head." The New York Times called her model a "full scale challenge to the reigning theory of immunology." Even The Wall Street Journal noted that, if accurate, her ideas ''would dramatically alter the development of anti-AIDS drugs, vaccines, and drugs to prevent the rejection of transplants." When she presented her case directly to nonspecialiststo veterinarians, students, clinicians, the publicthe response was electric, When she presented within her field, the response was fierce. Her detractors wrote angry letters. Johns Hopkins University historian of science Arthur Silverstein bristled. Calling the questions nothing new, he added: "it is unclear how the inferences and conclusions drawn by the authors could have passed peer review." Others started off with more common criticisms: They were "overinterpreting their findings," said Charles Janeway. They confused the age of the cell with the age of the organism. All she had shown was that she could get an infant mouse's immune system to react, But

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Janeway took deeper issue with her proselytizing to a lay audience, and so did others. "Maybe it's too close to the field's roots as in snake oil salesmen, or alchemy," suggested Ron Schwartz. The reaction was insidiously backhanded. In 1995 for instance, she was in Australia to present at a conference, and the BBC was filming for a special on her called, "Turned On by Danger." Several researchers assailed her in the seminar, but only one would go on camera. The reaction seemed the response of a field whose main foundation is challenged by "an ontology," said a supporter, Rochester University hematologist Neal Blumberg. Fuchs and Matzinger fired back a defense in Science that noted how, almost two millennia before Copernicus, Aristarchus had proposed a heliocentric universe, only to be laughed out of the academy until the academy was ready to hear the news. They cited Thomas Kuhn in defense of the strength of their new paradigm. The difference in their idea, they said, was that their theory explained anomalies in Medawar and Janeway. Some of the reaction did not make sense: Silverstein, for instance, said both that they were wrong and also that they were adding little new to the old model first proposed by Burnet. Which was it? they responded. If their idea linked them with Burnet, they wrote, "we could be in far worse company." But the tempest had another effect: more than ever, Matzinger resolved to go over the heads of the arbiters of field. Instead, she pressed her case directly to clinicians, students, and the public. In 1997 she was asked to give a Special Topical Lecture at the American Association for the Advancement of Science meeting in Seattle, where Venter and ecologist Gretchen Daily also gave major talks. She logged 100,000 miles in three years, breaking into the public domain much as Greenfield and Venter and Marcy were doing. The difference was, she sought out the publicity to motivate the acceptance of her ideas. In 1998 she was talking to veterinarians in Ontario, to genomicists at the Institute for Human Gene Therapy in Washington, to researchers in Boston, New York, Amsterdam, Sydney, and Auckland. Proclaiming her ideas to the world in the BBC documentary, in press articles, in an Elle magazine profile written by Cynthia Fox, she further enraged her critics in the field. "Polly is doing this kind of sales pitch. She's very good at it. Many scientists react to that as not science, though," her friend and NIH supervisor Ron Schwartz commented, likening her to a kind of "Madonna figure," It was not just a new idea but a new way of offering ideas in a period of tremendous change in the access of scientists to the media. "It could be that the legacy of [people like Matzinger and Venter], these

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prophets of the new frontier, is that they're open to teaching the public," said Schwartz. Her talent for promoting her theory, not to scientists but to the general public, further exasperated her critics. Charles Janeway said, "The bottom line is there are thousands of researchers doing important science in this field, and Polly is not one of them." To others her penchant for publicity undermined the seriousness of her approach. "I think this accounts for the utterly disproportionate anger I'd hear in the field. People ask me, how can you keep her at the NIH? Well, from the start she's done very careful, very seminal experiments," said Schwartz. ''But people do not accept this. Why?" The theory pushed immunology to look inward, urging researchers to attend differently to each organism, which was part of Matzinger's talent for training dogs but ran counter to the drift of Western science, "She said you should make a different vaccine for each patient, and medicine was not ready for that," observed Pramod Srivastava, a University of Connecticut immunotherapist. "She's given a vocabulary to contain thoughts that perhaps were not being thought about. She said the words. Words are like trap doors. They can let you into new rooms, new universes. The language she used for danger is a very powerful trap door." The larger community of science recognized the "trap door" intricacy and freshness in her contribution that engendered the anger in her field. The journals Science and Nature invited her to review papers for them. She became a regular review contributor to Nature, as was Susan Greenfield. She served on grants review panels at the NIH. She became a much-sought speaker at major conferences, especially those outside the conservative, datadriven United States. Multilingual and multidisciplinary, she connected with European science in a way none of her rivals did. She became the first woman ever to give the prestigious Grabar Lecture at the annual meeting of the French Society for Immunology. She gave keynote addresses at the German, British, Canadian, Austrian, Scandanavian, and Dutch immunological societies, as well as at the annual meetings of nonimmunologists in the United States, including geneticists, ethicists, and transplant surgeons. But, in the end, was she right?

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6 "No number of lectures, seminars, or other verbal communications," Peter Medawar wrote in Advice to a Young Scientist, "can take the place of a contribution to a learned journal." Arthur Silverstein suggested there was no way to test her theory. With her international travels, she was slow to build the data she needed to convince her field, but other researchers that she hooked took up the slack. These included Gus DalGleish of St. George's Hospital in London, Allan Kirk at the U.S. Naval Hospital in Bethesda, and Pramod Srivastava. Allan Kirk and David Harlan of the U.S. Naval Medical Research Center were among the first to jump on Matzinger's idea. Kirk began working on kidney transplants, making them "take" without using immunosuppressive drugs, as the danger theory promised. He had promising results in mice and moved on to rhesus monkeys. By August 1997 he was announcing results of an experiment using a synthetic protein that made it possible for an immune system to tolerate a mismatched kidney without any immunosuppressive drugs, and the story was big enough to make it into The New York Times Science Section. By June he was holding a press conference to confirm what Leslie Spring of the National Kidney Foundation called "an amazing breakthrough," the use of synthetic antibodies to mimic a safety signal in rhesus monkeys. In November 1998 the technique was providing a model that could be applied to the autoimmune disease Type I diabetes, and Kirk joined with the Diabetes Research Institute at the University of Miami to develop a human treatment. "We lose ten people every day because I'm not working fast enough," he told reporters. By February 1999 the National Institute of Allergy and Infectious Diseases inviting him to join an expert panel to develop "a new paradigm'' to revamp the dialogue between clinicians and theorists like Matzinger. Gus DalGleish of St. George's Hospital recalled being electrified by Matzinger's talk at the American Association of Immunology Conference in New Orleans. He had been treating melanoma patients with a vaccine created from their own tumors, and Matzinger's theory provided a new framework to explain the results: the immune system had to be stimulated to see the tumors as dangerous. Within two years he was seeing a threefold increase in the survival rate of his patients. "It's not stopping the disease," he cautioned, "but it's slowing it so one can go in and remove the tumors." As for the other cancers, Matzinger had success in convincing major researchers, like Michael Lotze of the University of Pittsburgh School of Medicine, who suggested that,

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her "strong intuitive sense for the biology is right and what she calls 'danger' is largely right." At the National Cancer Institute, researcher Francesco Marincola suggested that her theory "explained a lot of phenomena molecular immunologists" were seeing. "The old model is definitely wrong," he said. "Matzinger's theory is a historic intellectual step. It's the only one going in the right direction." But she still needed her molecular handle. She got one hint from an unlikely place. In India many years earlier, the budding paleontologist Pramod Srivastava had been helping temporarily in the Center for Molecular Biology, where he puzzled over the fact that a cancer vaccine worked against only the single tumor it came from. "What molecule could be so valuable, so polymorphic, as to account for this?" he wondered. Thinking he might be onto the discovery of a mechanism as profound as that of antibodies, he began doing experiments. Not knowing immunology, he came at the problem as straight biochemistry. What he was led to was very humble, not antibodies at all but a kind of protein called "heat-shock" because cells manufactured more of them when they were heated. Because heat-shock proteins could replicate the antigenic handle on a tumor, they appeared to be the body's internal mechanism for signaling. Srivastava had been thinking about his heat-shock proteins for about fourteen years, when he came across Matzinger's article for the 1994 Annual Review of Immunology. The danger metaphor caught his interest because it offered a "very powerful" new way of thinking about his own work. "I remember just feeling quite excited. It seemed that there was something important for me in that idea." Coming from India, he felt her idea of the way cells died held an important message. It "resonated very deeply," he said. Rather than a lockstep immune system, Matzinger saw a flexible system requiring flexible, personalized treatment. At the 1995 summer International Immunology Congress in San Francisco, one of his postdocs who had heard her talk came to him, breathless with excitement. That was it: Srivastava had to call her. The beauty to him was that she confirmed his own shift of focus from outside to inside. Before that, the immune system had always been considered to be outward looking in the old technical approach of self/nonself. "Hers was this very powerful idea, to listen to what the body is telling you. I found it very powerful scientifically, as far as its testability and implications, and metaphorically as far as its admonition to return to a traditional medicine of close observation. I felt the objections to her were mainly a cultural block."

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Like Kirk, Srivastava set to work, first with mice, then rats, then sheep. By 1998 he was hosting the first International Conference on Heat-Shock Proteins, with another scheduled for 2000. He cofounded Antigenics, a biotech start-up, and prepared for clinical trials. He became involved in a series of studies at New York's Memorial Sloan Kettering Medical Center and Houston's M. D. Anderson Center. Small numbers of patients suffering from melanoma or renal or pancreatic cancer were treated with vaccines made from their tumors after they had been removed, with promising results. The trouble was that the procedure was expensive. Still, other biotechnology companies, including Intracel in Rockville, Maryland, were following up on the idea, putting them into the pages of The Lancet and on the front page of The Wall Street Journal. The danger theory offered one of several possible avenues for clinical treatments, and Srivastava did not see it so much in conflict with Janeway as extending his ideas. Yet within her field Matzinger 's ideas remained more problematic than they should have been. Paul Lehmann of Case Western Reserve University, for instance, tested the validity of her theory against Janeway's. In the summer of 1999 Lehmann published his findings in the Journal of Immunology. Of the three possible interpretations of what he saw, Janeway's idea he felt was proved the most wrong "because in the absence of bacterial products you still get immunity." Matzinger's was more likely accurate, but a little too simple and clean. "Danger is not a single quality," Lehmann cautioned. But for her contribution to shaking up the field, he was effusive. "Thousands of labs depended on self/nonself discrimination, and she suggested they reconsider this. She's done a wonderful thing," he said. Her theory worked well for clinical hematologists Joanna Heal and Neal Blumberg, who wrote letters to Science supporting her work. As for Matzinger herself, the dispute bothered her even as she stuck to her challenge. "Janeway's theory cannot explain why the immune system rejects transplants. I can." The debate could be boiled down to scientific issues, but the dismissiveness and the rancor were difficult to understand. "I used to be really close friends with Charlie Janeway," Matzinger said. "It just makes me really sad." There was nothing new about scientific rivalries spurring research. "The kind of rivalry between Janeway and Matzinger, that's the real history of science," said Schwartz. Nor was there anything new about a proposed theory outstripping the technical proficiency of the day. When Copernicus proposed his new theory of the heliocentric solar system, his idea could not be tested, wrote historian of science Karl Popper. It first of all offered a new way of interpreting old findings.

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"That was also true of Einstein and Darwin at the time of their findings," said Northwestern University historian of science David Hull. "There was no way at that moment to test their findings." Neil Blumberg, perhaps too glibly, called the objections to Matzinger a typical response of the "professional scientist heavily invested in an old model." Part of Matzinger's effect on immunology came from her international stature, which inspired a generation of students. Her nurturing passion attracted the minds of Kamala Tirumalai, who came from Madras just to work with her, and Oral Alpan, who came from Istanbul. Tirumalai was impressed not so much by her big-picture thinking but by her incredible command of detail. "In my first experiment I had amassed all this data," she recalled. "Polly spotted right away the three anomalies in all the tables that made for my conclusion." When Matzinger needed more direct proof of the danger model, Tirumalai and Alpan proposed an experiment with sheep. They hoped to answer a challenge made by Mel Cohn, to show that organisms can be immunized against their own proteins,"which would be one of the most direct proofs of the danger theory," says Alpan. The three of them, working with one of Matzinger's border collies, began heading out once a week to immunize their sheep and test their blood. "There are days when you're in the lab until 3 AM," says Alpan. "But the main thing she demonstrates is a way of thinking science. We're not here just to publish. She wants you to go out and spend a day at the ocean just thinking about if what you're doing is important. Then she listens.'' Matzinger offered a counterweight to the technicians of science who loomed preeminent at the millennium. An outsider, working with a small team, she brought a holistic approach to transform a field. "It is not the correctness of a theory which I wish to discuss, but its boldness," Karl Popper wrote. Great scientists, seeking the levels beyond the levels of reality we see, engage almost in a kind of mythmaking, Popper said. They build on what comes before. During a normal week, all three of them would bring her border collie in a Toyota Corolla to round up the sheep they would inoculate, preparing the data for a future paper. "She makes you excited about what she's excited about," said Kamala. I felt that excitement when she asked my opinion of what other researchers had said of her. She made me feel that I was helping to advance research in much the way she made me a co-conspirator in her story of a mysterious police detective, in what Schwartz said of their late-night talks. The final summer of the millennium for her

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included dog training and sheep-herding contests almost every free weekend. On Saturdays she was out in dewdrenched Maryland fields, moving through the mist. There was a revolution going on in the way we think about transplantation biology, and researchers like Matzinger were coming at the problem from science's humanist beginning. From the beginning of her own education Matzinger had questioned immunology's half-century-old model, but it was not until she read some good books on evolution that she was prepared to think creatively about that model. She left questions on a board and listened when one of her younger associates, Ephraim Fuchs, responded. Like the young cosmologists featured in the next chapter, she participated in a regular journal reading club with all of her assistants, keeping up on the newest questions both inside and outside her discipline. Her new model offered a highly fluid, interactive, discerning immune system that changed as an organism changed. It introduced a body operating by dynamic processes rather than the fixed rules of immunology doctrine. Moving between small picture and big, professional audiences and the public, she had presented both a new way of thinking and presenting one's thinking. "I can't think of another scientist who has been more influential in helping me make sense of the phenomena I observe in the clinic," noted Alan Kirk. What seemed impossible seems very possible now."

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How Much Fun This Is: Saul Perlmutter and the Supernova Cosmology Project 1 Graduate students called the home of Nobel Prize-winner Luis Alvarez "The Castle." Monday nights they raced there after their afternoon seminars and quick dinners, climbing the steep flagstone steps beneath low-hanging clouds, as drizzle raised the scents of bougainvillea and pine high in the hills of Berkeley, California. Inside, they could hear arguments rage in the living room with its baronial stone fireplace and commanding view of San Francisco Bay, as senior researchers tried to prove each other wrong. Everyone ate Oreo cookies and gulped slippery beers, watching as casserole dishes were tilted to imitate the Earth's axis or the curve of gravity. The terror of the meetings was that each week one student had to report on a new finding or hot science rumor. Alvarez and the others would grill the speaker, interrupting every few minutes, demanding clarification of a statistic or contradiction, until gradually the group moved on to the latest controversies and gossip in physics or science or just about anything. Tall and blond at seventy, Alvarez had won a Nobel Prize for the particle physics discoveries made with the bubble chamber he had invented. Since then he had moved among different fields, looking for fundamental questions. He started companies and they succeeded; he started branches of physics and they caught on. He could have rested on his achievements, but instead he lunched

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with students (the "young pricks" he called them) rather than colleagues ("old farts"). He worked with undergraduates and graduates. He invited them to his home. Once Alvarez invited physiologist Marion Diamond to dissect a brain on his coffee table. When she was done, Alvarez squeezed the cerebellum, then tossed the rubbery lump into the air. The lessons of those evenings boiled down to one thing: all science is crazy passion. Into this group in 1982 came twenty-two-year-old Saul Perlmutter, a hawknosed, long-haired, slight, nice, quicktalking Harvard graduate raised near Germantown in Philadelphia. On those Monday nights he watched and absorbed the many lessons. If a mystery lay outside your field, he learned, you did not give up. You learned the new field. It was better to have a wide-ranging curiosity, to know a little about a lot of things, than to know a lot about a little. Most of all, he absorbed the confidence to shake up new fields if that was where desire took him. Perlmutter had been raised by two graduates of the academy: his father was a chemical engineer and his mother a social worker. Though Jewish, he had attended a Quaker school in Philadelphia. He played the violin and lived on a tree-lined block with working-class and professional families, playing baseball in the street and rooting for the Phillies. The idea of pursuing truth across many fields energized him. Saul Perlmutter wanted to pursue fundamental physics but felt depressed by its unwieldy bureaucracy. In the 1980s high-energy physics was practiced by four-hundred-person teams, working on the world's three or four biggest particle accelerators like the anonymous builders of gothic cathedrals. As a child he had loved building Rube Goldberg contraptions based on nature's simplest mysteries, like the way a rotating bicycle tire turns against the direction you push it. He came to California for big questions, innovative science, and for the Lawrence Berkeley Laboratory (LBL). Perched at the top of a steep hillside, the Lawrence Berkeley Lab was a unique government institution. Founded in 1931 in an abandoned clapboard engineering building, it helped pioneer a new science of nuclear cyclotron physics that cut across the traditional disciplines of chemistry, physics, and engineering. By the 1980s however, Lawrence Berkeley Lab physicists were again looking to a new interdisciplinary science. This time they were getting into cosmologythe study of the universe as a whole, its beginning and end, the kinds of big questions once relegated to philosophy. Probing infant galaxies, distant star clusters, tidal nebulae, and dying stars, they hoped to learn about the size and shape of the universe and, therefore, its age, without the aid of

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billion-dollar budgets and physics machines. In the very distant and the very large, conventional physics broke down, making fertile ground for basic research. Toward that end, the lab was developing the technologies for using a monster telescope that it hoped would be built at Hawaii's Mauna Kea peak, Looking into the deepest recesses of the heavens the Keck, it was believed, would capture the pyrotechnics of deep spaces power physics, much as the early Berkeley cyclotron had done for earthbound physics. At Berkeley Perlmutter met an enthusiastic Californian, Carl Pennypacker, who specialized in cosmic rays. With his moustache, glasses, and awkward speech, the twenty-two-year-old Pennypacker would lug fifty pounds of equipment up a mountainside in the rain if he had to. In sixth grade, Pennypacker had worked out for himself the mathematical proof that the square root of 2 was always irrational. He never forgot the incredible rush that he felt, in his room, unveiling a law of God. Seeking that same adrenalin rush, he joined Alvarez's group as a Berkeley undergraduate. Perlmutter and Pennypacker worked primarily for Alvarez's protégé, the Bronx-born Richard Muller. On those Monday nights of beer and cookies, they watched "how Luis's mind worked," said Pennypacker. They saw an independent, impatient, intuitive thinker, willing to admit his mistakes but ready to savage those of others. Alvarez thought the plan of American physics for a giant Superconducting Supercollider was ridiculous, for instance. He considered the $4-billion, twenty-mile circular Texas tunnel a machine with no imagination. Indeed, its final political defeat after millions had already been spent signaled the demise of cold war, big science. Watching Alvarez, the two graduate students witnessed how such a bold approach could transform a science and capture the popular imagination. Back in 1979 Alvarez's son Walter, a geologist, had discovered an odd layer of black dust containing rare isotopes of iridium and niobium in rock that was some sixty-five million years old. Other similar discoveries around the world seemed to link the dust layer, which could have been generated by an asteroid impact, with the extinction of the dinosaurs. Luis and Walter Alvarez proposed just that: an asteroid collision had blanketed the Earth with dust, obliterating the sun, lowering temperatures, and killing off the dinosaurs. The idea, cutting across disciplines like climatology, geology and astronomy, electrified the world, enraged traditional researchers, and eventually made the front cover of Time in 1985. The idea that such a tiny clue as a layer of dust could hint at such a profound secret of existence, exploding into the world's attention,

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grabbed hold of Carl Pennypacker and Saul Perimutter, who watched the drama unfold. "We learned there was no limit," Perlmutter recalls, "and that you could use one field to change another." What could they do to match that? They decided to attack cosmology, For much of the twentieth century, cosmology had been dominated by a handful of great men with access to the big telescopes on Mount Palomar and Mount Wilson. People like Edwin Hubble and Allan Sandage controlled the libraries of carefully culled photographic plates that built the dogma of galaxy classifications and the supposed expansion rate of the universe, its birth and fate. They uttered pronouncements like "Nebulae are found both singly and in groups of various sizes." As the writer Dennis Overbye observed, "You could hear the intergalactic winds creaking" through their prose. For all the swashbuckling at LBL, students felt haunted by the suspicion that this great triumphal era of astronomy was ending. There were many more physicists and cosmologists than ever before, and funds were drying up. Some told students that there was nothing left to discover. "The kind of research that made science grow for so many years, where you bring in young people and nurture them and they become great scientists, boy that's becoming very hard," observed Muller, after the tremendous success of his early career. "When I started in 1969, I could look around and see a lot of people having a wonderful time. I don't think that's true anymore." Then Saul and Carl came along. 2 Cosmology in the second half of the twentieth century was the quest for two numbersthe expansion and deceleration rates of the universe. If you knew those you could figure out the greatest mysteries of all: how the universe began and how it would end. The problem was measuring these numbers. What sort of yardstick could an Earthbound observer use to measure the expansion rate? In the 1950s an eccentric thinker at Los Alamos, Stirling Colgate, suggested the best measurements might come from supernovae, or dying stars.

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When a massive star runs out of nuclear fuel, its outer layers collapse onto its core, setting off a final catastrophic explosion. For a few seconds, it gives off more energy than all the stars of an entire galaxy. For the next three or four weeks the spectacular death cloud glows with the brightness of ten billion stars. The dying star spews out a rich dust of carbon and complex atoms, seeding the universe with the building blocks of life. We are all walking stardust or, more prosaically, the garbage of supernovae. Scion of the toothpaste family, Stirling Colgate became known at Los Alamos for concocting schemes that were either crazy or way ahead of his time. Supemovae could be seen very far away, Stirling Colgate observed. They also seemed to be fairly uniform in brightness, which depended mainly on what kind of star they originated from. Brilliantly radiant, they could serve as the calibrated candles cosmologists desperately needed. Colgate built his own automated telescope to search for supernovae. For cosmologists willing to take on the biggest questions, distant supernovae posed a quixotic goal. If you could somehow find and measure those superbrilliant explosions on the edge of the universe, you would have a shot at learning the age and fate of the cosmos. Indeed, in 1977, in a popular book called The First Three Minutes, Harvard physicist Steven Weinberg was among those who carried Colgate's idea further, suggesting that one should try to measure the redshift of the spectra of distant and relatively uniform supernovae. Redshift is a measure of speed based on the Doppler effect: the light waves from rapidly receding objects are longer than those of a stationary object, shifting their spectrum toward the longer, red end in the same way that the sound of a receding police siren shifts down in pitch as it races away from you. If one could measure the speed of the most distant observable objects in the sky, said Weinberg, one could learn how fast the universe was expanding and, thus, critical facts about its age and beginning. Astronomers knew all this; the problem was finding the distant supernovae and measuring their light. Until the twentieth century we could not hope to spot them. Observers on Earth with the unaided eye saw only about one supernova every few centuries, and these were close by. With better telescopes the search for dying stars became a quest for amateurs like Robert Evans, an Australian priest who tracked them in his backyard, using a ten-inch telescope. Evans memorized each sliver of sky, seeking any short-lived brightness that appeared where no star existed. His years of searching produced some forty supernovae, none of them very distant. He demonstrated what could be accomplished, however, as Evans helped mark a twentieth-century comeback for amateur astronomers.

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Hearing of automated military telescopes that tracked the sky for incoming missiles, Luis Alvarez proposed a systematic automated search for supernovae, using robotic telescopes to scan the sky and computer programs to compare fresh images with old ones, identifying objects that were not there before. But he was too embroiled in the controversies over the dinosaur asteroid to follow up on the idea. Richard Muller started a supernova search group with Pennypacker, but they had less success than Evans when they began. In their search for a big project Pennypacker and Perlmutter grabbed supernovae. "We always had in our heart and minds to use these to measure the universe," said Pennypacker. "Because that's the Holy Grail of cosmology and, you know, a major intellectual, cultural achievement if we could get that." They bet that improved computers, with more automated telescopes and sharper video light detectors, could raise viewing power exponentially. "We came from a generation that was comfortable with throwing a computer at a problem," Perlmutter said, In conventional astronomy, taking a spectrum of a distant starfiguring out what it was made of by breaking up its lightcould take a month. With new sensitive electronic detectors, spectra could be nailed in minutes. At least, that was the idea. More than simply a line of research, it was a new way of doing astronomy. They would go into the night without an agenda; the sky would tell them what to do. High-speed computer programs could digitize the information immediately, enabling them to send it around the world (first by fax and later by e-mail), then instantly command two or three of the world's best telescopes to focus simultaneously on a distant star's three-week death dance. That way they could increase their viewing power enormously. Huge amounts of data, near instantaneous processing, wide fields, state-of-the-art detectorsthe whole project was an almost ridiculously daunting adventure. It was guerilla astronomy. Fortunately they were at the Lawrence Berkeley Laboratory, where they could get the initial funds without a huge review process. Muller contributed some of the money that flowed in from some of his other grants. Pennypacker initiated the search. A Danish group had tried a similar approach but they lacked the followthrough and technology and support. "It's similar to genomics," said Harvard's supernova specialist Robert Kirshner, "in that the technology progressed very rapidly." In the hills near Berkeley, Pennypacker helped automate the University of California's humble Leuschner Observatory. A three-quarter-meter telescope, every minute it looked at a different galaxy. From 1986 to 1989 they found twenty supernovae among nearby galaxies.

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For distant supernovae they needed the newest technologies in charge-coupled detectors (CCDs) sensitive to ultralow light levels. Light was collected on a silicon wafer and then read out by a computer. A good photographic emulsion might capture 5 percent of the light hitting it; a CCD nabbed 50 to 80 percent. Their Monday nights at Alvarez's house gave them a secret weaponcultivating insiders at nearby Silicon Valley, they heard about and nabbed "the very best new detector the moment it came out," said Pennypacker. With their small early success, Pennypacker used LBL funds to collaborate with Warrick Couch to build a new camera on the Anglo-Australian Telescope. The camera was one of the widest-field systems on a large telescope, and it was dubbed the Pennypacker F/1 system for its new optics. They enlisted a senior data expert, Gerson Goldhaber, who had survived Nazi Germany and helped to discover several fundamental particles at LBL. With his white beard, Indian shirts, and calm deliberative manner, ready to plot their data points as he had plotted the bursts of energy in the earliest particle accelerators, he brought a steadying hand to the small, nervous group. They needed better computer programs, Muller said. Perlmutter had already developed them, "I decided then that Saul was directing this project and, since I wasn't ready to be a follower, I dropped out," Muller recalled. Australia made for an idyllic four months for Pennypacker and his wife and two children. It was like America in the 1950s. They were living the best of what science could be: you get an idea, get money, travel, and spend a year looking at the sky. In a beautiful national park high atop the hills east of Sydney, Pennypacker set to work. Once he had the machines up and running, he transmitted their data to Berkeley by a fledgling Internet link developed by NASA's AMES Research Lab. Driving home, he would see kangaroos skipping along the highway. They struggled, however, with poor sky conditions. When you observe through a computer you do not see clouds, you see lousy numbers. Frequently they told their operator to go outside and just look up to see why their programs were not working. The clouds prevented them from finding a single decent supernova. It was a disaster. "We almost gave up," said Pennypacker. Instead, they rethought their entire approach. Even if they had had better conditions, their technology was still not good enough to find the incredibly faint smudges they sought on the edge of time and space. They built a new camera from scratch, making the most of Perlmutter's skills as a young engineer in his family's garage, and sought a collaboration with the Royal Greenwich Observatory in the Canary Islands. The Cambridge group there was studying quasars

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distant, mysterious sources of gigantic energy pulses. "I said, why don't we work together and use the data for different purposes?" Perlmutter was proving adept at coaxing precious telescope time, becoming an operator and politician in their desperate days. In the isolation of the Canary Islands' remote mountaintops, with their howling winds, their collaboration began. The Canary Islands provided an ethereal backdrop for staring into the farthest reaches of the sky. At the top of the mountain, as in the film Journey to the Center of the Earth, eerie lava formations towered over a volcanic crater. At night the stars blasted out at full volume. The Milky Way glowed like a torn bridal dress. There they got their first supernova with the new telescope in 1992. It took three weeks, but once the data had been analyzed they knew something vital: the idea worked. The collaboration with the Royal Greenwich was vital because the Supernova Cosmology Project, the grandiose name they gave themselves, was under fire from their funders in the early 1990s. They had spent a lot of time and money in Australia and gotten nothing. Theirs was not a project that would pay off in a year or two, they argued. It might take ten. They said they wanted to do a new kind of digital, holistic astronomy. They would use the developing Internet to coordinate the search in the Canary Islands with the world's best telescope, the LBLdesigned Keck Observatory in Hawaii, and with the Hubble Space Telescope itself. Still the project was placed under external review. "We were fighting for our lives," recalled Pennypacker. On the review board was Harvard's Robert Kirshner, the highly respected supernova researcher. Because Perlmutter had been trained in physics, he struck some traditional astronomers as an interloper. The problem, according to Kirshner, was the huge uncertainty in the search. He pointed out that not all supernovae have the same brightness. "By 1991 we'd found a bunch that were extra dim and extra bright. It would be like looking at lights on a highway and not knowing if you were seeing a truck or a flashlight on a nine-volt battery," Kirshner said. "While Saul kind of charged ahead, some of us were very worried." Their rate of supernova discoveries was discouragingly low, he wrote to the National Science Foundation and the Department of Energy, and the margin for error in interpreting their brightness unacceptably high. The review caused a snowball effect that threatened the whole project, "We had to fight like crazy to keep it alive," remembered Pennypacker. Kirshner, he felt, "was leading the charge against our survival."

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Some good results came from the struggle, however. They recruited from their Cambridge collaborators a young, even-tempered spectroscopist named Isobel Hook, who thought their search was the most exciting thing in astronomy. She agreed to analyze the spectra of light from their supernova, telling them if what they had was a very distant, or ''high redshift" object. They decided to make their main telescope the Cerro Telolo reflector in the Chilean Andes. Viewing conditions were better there. When the external review finally proved favorable enough to continue, they started turning out distant supernovas. "By 1992 we got our first one, and by 1995 we found seven," Perlmutter said. Seven exploding stars, anywhere from six to eight billion years old. Our own sun was a second generation star, formed from the debris of objects like these. Perlmutter spent much of his time either in front of a computer or on the phone, cajoling extra viewing time from other teams sharing the telescope, in much the same way he had jerry-rigged his childhood Rube Goldberg contraptions. It was unbelievably difficult. Who would have thought of the great Luis Alvarez having to wheedle time from a competitor? But even Alvarez, now seventy-four, agreed to assist them, by pitching in to manually check their data, a time-consuming, arduous task. Perlmutter had such a childlike enthusiasm he was often successful in getting other senior researchers to cede prized telescope time, despite the fierce competition for it. Because they were not trained as astronomers they brought in a supernova expert, Alexei Filippenko, who had a knack for getting attention. With his bushy eyebrows and open face he was a favorite of undergraduates at the University of California at Berkeley, demonstrating concepts by throwing a tennis ball into the air. He could also offer them institutional access to Keck. He and Perlmutter, however, had egos that did not mesh well. Their nights were much more pressured than those of traditional astronomers, "heart-stopping, heart-sickening ventures," as Kirschner later put it. Nervously they watched and waited, ready to take whatever the sky gave themwhatever blew up. It was a heroic and unlikely method: first, one team at the Cerro Telolo telescope in the Chilean mountains ran the search, taking the CCD images. Then, three weeks later, Chile took a new set of images, and they transmitted the data back to Berkeley, using a compression technique because the Internet was not fully established. A team in Berkeley compared the two sets of readings. They either called them into the newly built Keck Observatory in Hawaii, or someone flew from Berkeley to Hawaii with the candidate list of supernovae. Then Hook and Perlmutter would look at the spectrum and trigger the data to telescopes around

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the world, including the Canary Islands, Chile, and a telescope in Arizonahoping what they had was a dying, unimaginably distant star. If not, they moved on to the next object. When they found something it was Hook's job to decide if the spectrum they got was indeed a supernova. With the whole team looking over her shoulder, she had a few minutes to give a thumbs up or down. When nothing was going on, Hook played rock and roll loud to keep them going through the nightVerve, maybe, or Radiohead. "I'll never forget the first supernova," recalled Hook. "It was at 1.4 redshift, not terribly high compared to what we get now, but it was such a beautiful spectrum and you could see every detail. There's no question that it was a Type I-A supernova. I mean it looked so good, it guarantees the project works." The image looked like a Mondrian painting. "Since then, we've been getting really good spectra at higher redshifts where no one has gone before. I think to the earlier generation (of astronomers), it seems sort of magic." With restored funding from the National Science Foundation, Perlmutter hired a few more postdocs and graduate students. The team now totaled twenty; they had "a presence." Some began giving papers at conferences. The Berkeley lab increased its support. At the end of a Keck telescope run, they would take time off to swim at Hapuna Beach, laughing and choking on salt water. At the end of the whole run, everyone came back to Berkeley from their distant locationsChile, Hawaii, Tucson. They gathered at the home of Gerson Goldhaber and held a party. For each supernova they found, they cracked open a bottle of champagne . . . eventually working up to twenty bottles. Success stiffened the competition, however, from inside and out. From inside, Carl Pennypacker realized there was no room for two group leaders and decided to pursue a project he had been thinking about a long time. He wanted to bring in public high-school students to work with the raw data the group used, giving students the thrill of cutting-edge discovery. Winning support from the National Science Foundation and the Department of Energy, he began the "Hands-On Universe" program. He sent their data to California high schools by Iternet, where students analyzed it virtually at the same time astronomers did. Students began discovering objects like new asteroids from the information, giving them a bit of the rush Pennypacker first felt doing his math proof as a sixth grader. He remained a member of the Supernova Cosmology Project, but turned over its leadership to Perlmutter.

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From outside, a rival international team of astronomers began copying their technology to compete with them. Calling themselves the High Z Supernova Project (Z stands for redshift), they claimed to be a looser, more sophisticated collaboration. They would pay closer attention to the nuancesthe precise filters and corrections needed to understand the exact nature of the spectacles they were seeing. They would gather less data but analyze it more carefully. Rather than cookie-cutter physics, they would practice real astronomy. Alexei Filippenko defected to join this group, led by none other than Harvard's Robert P. Kirshner and his former student Brian Schmidt. "The other group took pride in the fact that they didn't know anything about the folklore of the field," said Kirshner. "Brian felt we could do what they were doing, only better." Both groups were pioneering a new astronomy combining "big telescopes, great communications, and great computing power," said Filippenko. Several other projects were also practicing this kind of interdisciplinary cosmology. The Sloan Digital Sky Survey was using robotics and computers to provide the first three-dimensional map of the entire universe with a sky search that, like Perlmutter's work, would be available immediately to amateurs by the Internet. Using new robotics, cheap materials, software, and basic artificial intelligence systems, NASA and the European Space Agency were planning several deep space probes to explore the universe's beginning. NASA's MAP (Microwave Anisotropy Probe) and the European Planck satellites, for instance, would in 2005 and 2007 map in minute detail the ripples in the cosmic background radiationthe echo of the Big Bang. Like the supernova projects, these linked particle physics with deep space astronomy by exploring how protons, neutrons, and electrons first formed out of the cosmic soup. "We're at the beginning of a new astronomy," said Alan Guth, the MIT theorist who in 1979 wedded cosmology and physics with his theory of inflationthat the universe expanded exponentially in first fraction of a second. Now astronomy was trying to understand what the universe was like in every moment of its growth. "When I was younger I thought these parameters were unknowable forever. Now they're within our grasp. It's amazing. It really is." Perlmutter had not invented the opportunistic, shotgun approach, but the international team he directed had made it work. But if the supernova cosmologists felt vindicated, they also now felt the hot breath of others gaining on them.

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3 In September 1997, sitting in his cramped office in Berkeley, Gerson Goldhaber was studying the group's data points, the end product of months and years of work and dreaming. On graph paper he had plotted points from all thirty-eight supernovae. He routinely looked at the grouping to anticipate what they were learning about the age and future of the universe. For months he had noticed that all the supernovae were piling up at the lower end of the scale, meaning they were farther away and farther back in time than commonly accepted theories of cosmic expansion would have predicted. He kept thinking that the bunch would spread out as their precision improved. Instead what he now saw was a giant spike, almost exactly like the spike he had seen forty years earlier when he discovered the fundamental particle called the mu meson. He nearly jumped out of his chair. What the spike showed was that, far from decelerating as all the astronomy texts claimed, the universe was actually accelerating. This acceleration had been suggested by only one person, Albert Einstein, who called it lambda and used it to counteract relativity's prediction that universe should collapse on itself. Einstein quickly abandoned lambda as being a preposterous cosmic fudge factor. But the data Goldhaber was examining said they were seeing some kind of universal constant, a mystery engine driving the cosmos. At a hastily convened meeting on September 24 they argued into the evening. Several on the team urged caution. They were just getting legitimate acclaim. They dare not blow it on such an outrageous finding. Better to wait, gather more information. "Gerson says he will keep working on this," the minutes of the meeting read. Then, in italics, Goldhaber was quoted as saying, "I've been known to make mistakes." In December 1997 Saul Perlmutter was staying up all night at the Keck Observatory. Taking camcorder pictures of the sky from the peak of Hawaii's tallest mountain was a lonely job. Oxygen was only 60 percent of that at sea level and the night sky, stretching over the observatory's twin domes, disoriented viewers at three in the morning. He had a constant headache. Every so often the telescope operator put on his down jacket, went outside, and slid through the snow to look up and check that the three-hundred-ton machine was pointing out above the clouds. Steam rose from a volcano. Above him, seven-billion-year-old starlight roiled and spun. They worked all night and caught a few hours of sleep in the day.

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Perlmutter and Hook again worked frantically, analyzing the images and directing where to point the telescope with nanometer precision. Ever since their meeting with Goldhaber their work had a new urgency. Perlmutter was going to present their findings at the biggest science conference in the world, the American Astronomical Society (AAS) conference in January in Washington. What would he say? He e-mailed the targets to the Canary Islands, Chile, Arizona, and California, and ultimately to the Hubble itself. Then they waited anxiously. Isobel Hook had a few seconds to analyze each image from the top of the mountain. They argued, talking with the telescope operator by video teleconferencer. When she had some time, Hook liked to go outside and look up at the starlight coming from the edges of the universe, all the way to where she stood at the volcano's bottom in a breeze that smelled of bougainvillea. Perlmutter dropped the phone to check the computer screens again. Hook and Perlmutter decided when they had a good spot, assigning the greatest telescope in history, the Hubble Space Telescope in orbit two-hundred-forty-five miles above them, to look at a distant smudge of a star in the throes of death. Using this approach to detect supernovae on the fly and transmitting this information around the world instantly, they were coming close to realizing their dream. They were also racing another group. They plotted their findings on a graph, matching the distance of the stellar explosions against their velocity as they were swept away by cosmic expansion. Their data made for a perplexing line. Everyone was buzzing about it at Hapuna Beach on their last day. The line curved up at its end, as Goldhaber had suggested, meaning that indeed the universe was not decelerating as all the texts said, but was accelerating. If it was real it would make the announcement of a lifetime. But their uncertainty was high; too many things could be wrong. Did they have the correct color measurements? Why did their analysis now disagree so much with an earlier one? Perlmutter caught a flight to Berkeley, where he had a morning layover to race to the lab, run the numbers, print out a poster, and race back to the airport, where he hopped a plane to Washington, D.C. with the graph stuffed in his briefcase, heading to the annual meeting of the American Astronomical Society. I saw him present his findings that January. He was disheveled, having just jumped off the plane after staying up all night. From devices as common as the light detectors used in camcorders and the Internet, he said, they had evidence suggesting that, contrary to theory, the universe would expand forever into a lonely infinite night. Reporters mobbed him afterward.

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Surrounded in the press room of the Georgetown Hilton, Saul Perlmutter was the star of the AAS meeting. He was offering a possible solution to one of the biggest questions of cosmology. Fortunately, four other researchers on his panel, using more conventional methods, had gotten roughly the same result. After he gave his talk, reporters clustered around him for an hour, asking question after question. How could you take the Hubble, writers asked, steer it into position, and watch the death of a star lasting all of three weeks, from seven billion years ago? It was a great place to report findings because the funding directors of the National Science Foundation and the Center for Astrophysics were all there. Their story played not just in The New York Times, but in newspapers and on TV news all over the country. It was enormous news, telling us that "some kind of new physics is happening now," Princeton astrophysicist David Spergel told The Washington Post. Perlmutter discovered that he possessed the traditional cosmological talent for publicity. But he chose to play down their more spectacular results. One reporter, James Glanz from Science, commented on the implied cosmic acceleration in their data while two others hinted at it later. In the hall afterward I joined Perlmutter as he hung out with some of the other young astronomers, still happy to answer questions, checking out what they were doing. For the rest of their lives, however, some in his small group would question their caution. 4 The following month a much smaller meeting was scheduled at Marina Del Rey in California. There both supernova groups were to speak. Acceleration, the idea that objects in space were moving faster and faster away from each other was a monumental discovery, on the order of Edwin Hubble's first observation, in 1927, that the universe was expanding. If the universe was accelerating, the entire foundation of physics was shaky. It meant a completely unknown force or energy was at work. The problem for the Perlmutter team was that their margin of error, or error bars, were still too great, they felt, to make such a stu-

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pendous announcement. But the competing group now had had access to their data since it had been announced. What should they do? At Marina del Rey Perlmutter showed their data with the error bars, saying they had "evidence" for acceleration but not proof. Then Alex Filippenko rose to address the group. Well, he began, savoring the moment, either you have a discovery or you don't. We have evidence, and our error bars are much smaller and better understood. We have for the first time real evidence of a new "antigravity" force at work in the cosmos. Afterward a commotion broke in the conference room. Again it was James Glanz of Science who got the story first, though other journalists soon followed. The curve on the top of the High Z graph pushed the cradle of physics off a cliff. "Somewhere between amazement and horror," said High Z coleader Brian Schmidt of the Mount Tromlo and Sliding Spring Observatory in Australia. "Magical," said Michael Turner, theorist of the University of Chicago. "It's crazy," said colleague Rocky Kolb, who compared the discovery of the missing matter in the universe to the Marx brothers movie in which more and more people crowd into a stateroom, leading to chaos. If the universe was expanding faster and faster, not only were the texts wrong, but something like 70 percent of the universe's energy was missing. This mysterious energy was driving the unheard-of acceleration. The finding was so amazing that many theorists balked, rightfully so. "Extraordinary claims require extraordinary evidence," cautioned Turner. "The competitive urges," added another theorist, "have driven both these groups out onto a limb where they shouldn't be." While the two teams set to work on supporting their claim, Alex Filippenko had to take off for a long-scheduled eclipse cruise, mostly for retired couples. It was fitting that the youngest member of the High Z team, the soccerplaying Adam Riess, suddenly found himself on the "McNeil-Lehrer News Hour" (his father's favorite show), discussing the meaning of space and time. "(They) asked me, 'Why should people care about this?'" Reiss recalled. "I said, well, 'Why am I on this show?'" Riess had done most of the grunt work. For once a postdoctoral jobseeker got the acclaim. Younger than any other group member, Riess was proof of a new astronomy taking hold. ''This was something most of us thought we would just never know," he said, echoing Guth's words. As for the Perlmutter team, after all their work, all the rejection, the criticisms leveled against them rankled: they were too bold or not bold enough, and in either case they were mere physicists, too sloppy for the finely nuanced art of astronomy. Kirshner gave them no credit

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in his discussions in the press, even though it was their method that made the discovery possible. "He got the credit because he came from Harvard," complained Pennypacker. "They have better press agents," said the normally equable Gerson Goldhaber. The bad blood between them, embarrassing for all, became even, well, badder. "Hey, what's the strongest force in the universe?" Kirshner told The New York Times. "It's not gravity, it's jealousy." Photographed in front of the august Harvard-Smithsonian Center for Astrophysics, he grinned in triumph. 5 The announcements of the findings had stirred up so much puzzlement and sheer disbelief that Perlmutter, Riess, and Kirshner were all called to a showdown at a conference in May 1998 at the Fermi National Accelerator Laboratory. In the Illinois prairie, theorists and experimenters came together for a gathering called "Where Is the Missing Energy?" The theorists were desperate to question and challenge the findings, and to know more. The giant particle accelerator at Fermilab provided a fitting backdrop, because it was the machine that solidified the last piece of the Standard Model of physics and the cosmos. While cicadas chimed outside, researchers grappled with the discoveries. If, as most thought, the cosmic soup had exploded exponentially in the Big Bang, doubling in size every instant in its first trillionth of a second, it seemed as though, for its first seven billion years, the universe had indeed been slowing down. The evidence from the supernovae experiments suggested, however, that at a critical point, when the density had lessened, another repelling force had kicked in, pushing matter out faster and faster. The force seemed to be Einstein's famous "cosmological constant," added in 1917 to his theory of general relativity. Einstein added it because relativity seemed to predict the universe should collapse under its own weight. When Edwin Hubble discovered the expanding universe, Einstein discarded his constant as "the greatest blunder of my career." Now it was resurrected, If the universe was accelerating, some previously unknown enormous energy existed.

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Was the missing energy Einstein's cosmological constant, or something more dynamic that varied over time? "It's a monumental issue," said Princeton's Paul Steinhardt. "It means a significant fraction of what's out there we weren't even thinking about a few years ago. That's why it's particularly important to understand whether it's something fairly uniform and static, or something dynamical and changing. It's monumental both for fundamental physics and for cosmology." What was going on? Steinhardt called the missing energy "quintessence," after Aristotle's fifth element. Quintessence was fundamental mystery, a roadblock that seemed a precursor to a radical shift in scientific thought. Was quintessence the same as dark matter, the unseen stuff that seemed to clamp down on galaxies like a waffle iron? It seemed not. It appeared rather, that this energy or force had an effect only after some seven billion years, during which time the expansion did decelerate as standard theory predicted. Once the density of the universe fell below a certain point, however, the "antigravity force" kicked insuddenly revving up the outward explosion of all matter. The answer lay in supernovae evidence. "Not only would it tell us what the universe is composed of, where it came from, and where it's going, but it would tie together the laws of physics," Paul Steinhardt said to reporters at a special luncheon at Fermilab. Over the clacking of plastic forks and whirring of tape recorders, he said: "It must emerge from a fundamental law of physics, and we need to know which form it is, not only for cosmology, but for people who are trying to develop the holiest grail of allunified theories of fundamental forces. You have a new ingredient that you had not anticipated suddenly forced upon you.'' Endorsing the new interdisciplinary approach, he added: "It's an opportunity for cosmology to provide a gift to particle physics." Within a few months the ground would shift once again, as more observations plotted on neat graphs, shown on overhead transparencies, and reproduced in Science and popular newspapers confirmed that the universe began to accelerate about halfway through its 14.2-billion-year history. What was this exotic energy that opposed the natural self-attractive gravity of matter? Whatever the answer, the two supernovae teams had taken the search for the true nature of the cosmos out of the realm of philosophy and into that of science. "In science you usually have a tradition you must match," said Perlmutter. "Do your data fit the tradition? In this field, there is no tradition, no previous data. It's completely uncharted." At the end of the Fermilab meeting, while Telemann from a state high-school flute competition echoed in Fermilab's great hall,

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Perlmutter and Adam Riess gathered over a coffee table, comparing problems with their graphs while the laughter and jokes of weary participants rose around them. The tension of the grilling in the conference was over, and Kirshner, Guth, Steinhardt, Turner, Kolb, and others made plans for Saturday night in Chicago. The Supernova Cosmology Project was still sensitive about the manner in which their technique had been adopted without credit being given. Kirshner and Filippenko resented their rivals' accusations. The tensions between the two teams were personal and emotional but, more importantly, they were philosophical: do you want fewer observations done more carefully or more observations done less carefully? Yet in the end, Perlmutter and Riess were just two young kids, scribbling on a napkin that I walked over and retrieved later, sipping coffee and trying to make a contraption work. Prior to the last decade of the twentieth century, new cosmology results came in rarely. Once every few decades some data would really change things. "We are now entering an era where we are able to probe simultaneously the universe in its very early times, intermediate times, and present time," said MIT's Alan Guth. "It's amazing, it really looks like in the next five, maybe ten, years, all the questions that seemed completely open all these years are going to be nailed down. I think in five to ten years we will know if the universe is flat or open or closed, and we will know quite accurately what the Hubble constant (expansion rate) is, and we will know quite accurately what the mass density is, and whether there's a cosmological constant or not. All those questions seemed totally open five years ago." Combining computers, robotics, the Internet, and video sensing, cosmology was heading either toward confirming what we think we know, or toward revolution. Not everyone agreed, however, that cosmology and physics were entering a new era. Lawrence Berkeley Lab's Richard Muller, for one, disagreed. "Louie Alvarez told me in the last few years of his life, that if he had to go into physics today, he would never make it. He said he just couldn't stand the bureaucracy." As to what Perlmutter had done, Muller said: "To do a project that takes as long (as Perlmutter's), you would not get the support today. Perlmutter was lucky he was at LBL, and still he paid a price. He had to give up faculty positions. He had to take personal risks, have a job where his salary would not be guaranteed, that kind of going out on the personal edge. There aren't too many people like Saul around these days." Even Perlmutter admitted it had been difficult, and wondered aloud where such innovations could come today. To answer that, one

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must look at how he did it himself. "Perlmutter was successful because he went after big questions," said Carl Pennypacker. "You forged ahead even though you did not know how you would pull it off. That was a gift from Luis. At LBL there was an atmosphere of support. You could be aggressive, because you got some money to begin." They were also close to several other industries and leading departmentsthey managed to get hold of the best cameras and computer programmers. Perlmutter had the support of parents and mentors. He and Pennypacker were opportunistic and practical, and lucky. At the time they started, the technologies of the Internet, the space telescope, the robotic and computerdriven searches all became viable. The confluence of technologies did not make the project inevitable, but possible. To make it happen he had the model of Alvarez, the resources of LBL, the guidance of Goldhaber, and even the rivalry to spur competition. He had also a rare quality of being genuinely nice that made people want to help. He cajoled extra telescope time around the world. He helped guide a large international team. Being nice, it struck me once again was almost a requirement of bold complex-systems science if you wanted to inspire others to your cause. At the end of 1998, Science named the accelerating universe the "Breakthrough of the Year," New supernovae were pouring in, and what was accepted as the team decided to name them alphabetically after classical composers rather than by numbers as they had been doing. By spring, they had Albinoni, Brahms, and clear evidence that showed the universe changing speeds. Of course, nothing in cosmology is ever completely clear. "What do you think of lambda Uncle Allan?" an astronomer asked Allan Sandage at a 1999 conference. "Not much," he replied. In 1600 Galileo Galilei, a thirty-six-year-old professor of mathematics at the University of Padua, heard of an instrument for making distant objects appear close. It was invented in the Netherlands out of spectacle lenses, but there it was used solely for military purposes. Galileo was the first to direct it at the moon and the sky, make systematic notebooks of what he saw, and shake the intellectual edifice of Europe to its foundation. Years before the Supernova Cosmology Project, a Danish team had pursued the same goal with robotic telescopes operated by computer. But the technology was not quite good enough, and they gave up. Each technological advance sharpened our vision of the cosmos, to the point it seemed we could uncover its precise age and, thus, a vital clue to its beginning. "We get an age of 14.2 billion years," Adam

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Riess told me at the Fermilab meeting. "To me, that you could answer such a thing is amazing. I mean, it started out that we thought we were the in the center of the solar system. So, okay, we're not at the center. Fine. So then we learned that the matter we're made up of may not make up most of the universe, it may be darker. Now we're," he paused as I looked at the napkin he and Perlmutter had been scribbling on, "now we may be learning that even the kind of energy we're used to thinking about, the kind of energy that affects us day to day, may not make up the majority of the kind of energy in the universe. So we may be totally unrepresentative in any way. We don't fit in, we are not normal, and our intuition could be totally wrong. We might not be seeing what most of the universe does, what most of the universe is made up of. I think that's quite amazing." Timing, the techniques of another discipline, technology, complex networking, and imagination marked the new cosmology. It did not seem to be the end, but the beginning. When I showed Perlmutter the napkin he had been scribbling on, he laughed. "What people don't realize," he said, "is just how much fun this is." The latest Supernova Cosmology Project proposal was to build an entire satellite, called Supernova Accelerator Probe (SNAP), to track two thousand supernovae a year and perhaps nail the exact identity of what seemed a new mysterious force in the universe. If the satellite was approved, it would be up and running by 2007, based on the successes of the two teams. Like two competing orchestras, the supernova groups worked from a confluence of several disciplines and approches and instruments to create a new era in cosmology. In fact, Perlmutter had just heard that planet finder Geoff Marcy played the cello, and he needed one for his string quartet. He was about to pick up the phone and call.

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The Art of the Woodpile: Gretchen Daily and Nature's Services 1 Three young women lived upstairs above their bakery in a cement building in a small town near the southern edge of Costa Rica. San Vito had a bullring where only fake bullfights took place and a few small grocery stores lining a main street with no streetlights. In the morning the smells of pastries like tres leches, or "three milks," rose like the scents of flowers outside the bakery. In the evening the odor of bread baking with cheese in the middle brought workers into the Panaderia from the coffee farms and ranches dotting the mountains, taking the time for a quick chat before dinner. Thirty-one-year-old conservation biologist Gretchen Daily found any excuse to stop by the Panaderia to eat a couple of cocadas, coconut sugar puffs, after returning from her work in the warm damp fields. She liked the women in the shop and often picked up vital information from them. Her favorite was Magaly Chaves-León. The bakery's sales of bread and pastries paid for her tuition at the local community college. She often asked about Daily's research. Lanky, with unruly blond hair and steel eyes, Daily rose before dawn to snoop around in people's backyards, farm fields, and bits of forest, carrying binoculars and a note pad to record the birds that thrived in habitats altered by man. Birds like the tropical gnatcatcher, blue-crowned motmot, scarlet-thighed dacnis, and different kinds of tanagers raised a huge call, like a symphony. "It's so beautiful it's almost like not working," said Daily's graduate student Jennifer Hughes.

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Daily was leading several experiments and collaborations that sought to fundamentally extend the study of ecology, centering on which species are likely to survive human impact. Directing a small research group, she was asking big questions about the complex interactions of nature and our role in it. Studying birds, moths, butterflies, beetles, and mammals, developing remote sensing by satellite of ecosystem health, she wanted to develop a scientific basis for the policies needed to sustain Earth's life-support systems. To some critics the questions were too big, the work too much a leap of faith. "You have to start somewhere," was Daily's reply. Humans were setting off the sixth great extinction spasm in Earth's history. Thousands of species seemed to be disappearing every year. Even one species lost contained an encyclopedia's worth of genetic information. If humans dominate the Earth, Daily reasoned, then scientists needed to study how plants and animals will survive in human-altered habitats. It was an integrative, interdisciplinary science of tradeoffs, asking: what was the net benefit or cost of society's protecting the next unit of an ecosystem? Indeed, what opportunities could come from the environmental crisis? Yes, the questions were so difficult as to be beyond the view of usual science. It was a lot easier to work in a laboratory. But that did not mean you gave up. For most of its history, ecology focused on pure nature in isolation from humankind. Landmark studies by Edward Wilson on the bees of the Canary Islands established the benchmark of "island biogeography," the study of species on secluded bits of land. This seminal work was the model by which all future work was measured. But the trouble was, most ecosystems rarely worked as isolated islands in a human-dominated world. Pollinators of wild plants and crops nested in town parks, vacant lots, or along railroad tracks. Nature in turn provided wealth to citiestheir raw material, pure air and water, flood and drought controls. Where others had studied islands, Daily studied interactions. She called her work "countryside biogeography." It was no mere academic debate. Daily's work, which put her in Newsweek's Century Club and on the front pages of newspaper business sections, was to help governments quantify the services of nature, as part of a tidal shift in the way we think about animals, plants, climate, and the proper human relationship to the fragile planetary skin on which we live. Whenever policy debates came up, the problem was that developers could always quantify the jobs and money generated by new construction. No one quantified the value of the lost services of nature, like climate regulation, protection from flooding and other

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disasters, or production of food and the ingredients of medicines. She wanted to provide governments with that accounting. "What was nature worth?" a New York Times profile of her once asked. "For you, thirty-three trillion dollars," it answered erroneously. Many changes were making her analysis of ecosystems services more and more of a possibility. First, new tools like remote sensors, advanced computer software, and satellite imaging made it possible to develop more and more complex measurements of nature's activity. Second, a new approach to doing science, combining disciplines like meteorology, economics, ecology, biology, and chemistry, made the time right for interdisciplinary researchers willing to take the risks. Third, Daily made a point of going outside traditional science to work with people from all walks of life and all over the worldbusiness people, mothers, villagers, movie producers, farm laborers. At the San Vito Panaderia and in the fields, she consulted the husbands who hunted and the children who knew the beetles and insects better than the hunters. The farmers explained which crops they planted and why. She insisted that her graduate students learn Spanish before coming. Daily was also one of the few ecologists who consulted with corporate and economics experts and leaders, trying to understand the problems through their eyes. She wanted nothing less than to throw off the old Romantic idea of nature isolated against humanity, an opposition as old as Wordsworth and as sweeping as Virgil and Plato. She had about a dozen such projects going at once. She was writing a feature on biodiversity and happiness for a National Geographic book, coauthoring three articles under submission to peer-reviewed journals on topics like her work in San Vito, writing grant applications, teaching undergraduates, making public appearances all over the world, advising the U.S. government, and devising partnerships for ecobusiness ventures. Any one of these projects was a few years out of a single career. "It's a curse," Daily said of her passion to pursue science that mattered, "but sometimes I feel if I don't do it, so few will." That she carried out her big-picture research in the public eyeon television, in radio, and in popular magazines was yet another risk she took. Some researchers criticized her approach as far too broad and sweeping. Others extolled it. "She's fearless. She's a hero to me," said her department chair, Harold Mooney. "She's what science should be," said her longtime collaborator Paul Ehrlich. It was not easy. Always she felt pressure: she should be doing more. She could be doing more. But it was not impossible, she said. What was the point of science if not to answer the biggest questions

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of how the living world was going to survive? At the Panaderia, she and Chaves-León talked about putting on a party. The women would bake and the scientists would hang out with the children. "Let them see what the blond lady does in the back yard," they decided. 2 The study of ecology and nature, and our place in them, probably goes back as far as human history. The ancient Greek Theophrastus wrote about the relation of living things to their environment in the time of Aristotle, and by the nineteenth century the infamous Thomas Malthus was plotting the fluctuation of human population with food supply. In the first half of the twentieth century, however, interdisciplinary ecology began to take off as botanists and biologists in Europe and the United States studied the flow of food and energy in natural systems. In the later twentieth century, the conceptual basis of a new science of ecosystems finally became widely accepted. It was the product of about a half-dozen other sciences, including climatology, microbiology, conservation, ecology, and population studies. It remained a somewhat suspect, hybrid science, retrospective and descriptive. When human pollution began threatening 3.8 billion years worth of evolution, however, the study of ecosystemsanimal, plant, geological, climatological, and human relationshipsbecame front-page news. The furor over air pollution, acid rain, algal blooms, declining fish catches, and death of forests was further ignited by the publication of biologist Rachel Carson's Silent Spring. About the time the furor was beginning, in 1964, Gretchen Daily was born in Washington, D.C. After living in the United States and Germany her first two years, her family settled in California, in the San Francisco Bay Area, where she grew up as a tomboy climbing trees and wandering the foothills encircling the bay. When she was twelve her father, an ophthalmologist, decided to show his children other parts of the world. He joined the U.S. Army to serve in the medical corps overseas. From him she inherited a pragmatic idealism and willingness to leap over boundaries that would serve her well.

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Her father took his family to Frankfurt, where she attended a private international school. She studied eight subjects, learning French and German as well as English. "I saw the difference between an American education and a really fine European school. I had a great biology teacher," she said. In the late 1970s, though, the dollar plummeted and her parents transferred her to a free Army school in Frankfurt. It was an early experience of the link between international economics and people's lives. One science teacher there was the school's main drug dealer. "On our first day of class he barely reached the Ds in his roster," Daily recalled. Still, some great teachers reached students, and Daily learned something of life in the real world. She also witnessed the explosive convergence of international politics and the environment. By the late 1970s acid rain had become a huge concern in Germany. News photographs of stricken stretches of the Black Forest earned the blight the ominous name Waldsterben (forest death). Daily did an all-year after-school project on pollution in a local river, winning an international high-school science competition. But still she had no particular ambition. Some school friends were skiing and putting off the Army. "I would have become a ski instructor," she said. "But my Dad wrote away for college applications. He made me apply to Stanford." With her straight As, she got in. Returning to California as an undergraduate she pursued first German literature, then geology. It took her a while to find her way into biology, where at first she felt overwhelmed. She was used to "doing nothing and getting an A." Now she was with people who already knew the material she struggled to learn. A deep insecurity set in, but she used it to drive herself harder than her friends. She joined the ski team and served as a docent at the local forest preserve. She lucked out by walking into the biology laboratory of Paul Ehrlich. The small, voluble Ehrlich was a major scientist who had put ecology on the map, for better and worse. With his wife, Anne, Ehrlich educated and browbeat the American public about the ill effects of the human assault on the environment. He attacked Americans' faith in superabundant natural resources. A big early success as an author was his appearance on "The Tonight Show" in 1970 to talk about his book The Population Bomb, which then became a bestseller. Authoring forty similar books, appearing a total of twenty-five times on Carson's program, he became one of the most visible public scientists in the country. He also committed gaffes that earned the enmity of many colleagues and conservative critics, offering scenarios

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for massive food riots in the 1980s, worldwide starvation, and a nuclear attack on the United States. In some ways Ehrlich's worst enemy was his mouth. But to Daily, Ehrlich was one of the few scientists willing to tackle the world's biggest problems in the public arena. He showed that a scientist could make mistakes and yet keep fighting in public for a cause. He and others also supported her. "I was lucky to have senior faculty telling me not to worry, it was risky and sometimes painful, but worth it." She joined Ehrlich's research group at the Rocky Mountain Biological Laboratory near Crested Butte, Colorado, where she proved to be resourceful in gathering data and in analyzing it in innovative and creative ways. She learned how to seize opportunities. One day, for instance, as she and Ehrlich were walking an alpine path, they heard a loud tapping in a willow. They peered inside to see a woodpeckera red-naped sapsuckerchiseling away at the wood. The bird continued without noticing them. As they watched, hummingbirds and warblers came along to get the sweet sap pouring from the chiseled bush. "This is great," Ehrlich said. "Stay here, Gretchen." She sat for hours, taking notes as chipmunks and squirrels joined the group. Thus began a study that would extend many months, into years, as Daily returned again and again to spend hours videotaping and recording, swatting flies and sticking to research that kept expanding. Eventually she demonstrated the subtle interactions of a fungus that weakened the trunk of aspen trees and a bird that nested in such trees, feeding on the sap it made flow from willows, with the communities of squirrels, chipmunks, hummingbirds, wasps, butterflies, and other species in the ecosystem. As it would many times in her career, a nature walk with a friend led to a study of complex communities of animals and plants, even when they seemed to have no obvious interaction. "The disappearance of a single species," she noted years later of that research, "could precipitate a wholly unanticipated unraveling of community structure." The first study produced her first published paper, cowritten with Ehrlich: "Red-naped Sapsuckers Feeding at Willows: Possible Keystone Herbivores." Appearing in American Birds eighteen months after she graduated with her B.S., it was a coup for a budding ecologist. She wanted to pursue her master's degree. In coursework she focussed mostly on math, but in research she rebelliously expanded, linking with several prominent women. Mentors are important to all who are young and creative, but they are probably more critical for women going into science. Baylor University mathematician Vivienne

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Malone Mayes, the first black faculty member hired at Baylor, has spoken of the significance of her teacher Evelyn Boyd Granville, one of the first two black women to receive a Ph.D. in mathematics in America. At Stanford, Daily answered an ad posted by the nonprofit Worldwatch Institute's Sandra Postel. She worked with Postel to investigate global warming, acid rain, and integrated pest managementthe use of natural predators to attack crop pests. Postel taught her to develop research that could shape policy, science that mattered. ''Even then," Postel recalled, "Gretchen was torn between which direction to gointo academic science or public policy." After graduating, Daily headed back to Germany, where she struggled to decide what to do with her life while studying the effects of acid rain. She realized that to make her mark in the world, academics was the route. "I could have gone into law or politics, but after watching Sandra I could see the battle she had to face," she said. "Science satisfies a lot of desires for me. It satisfies my curiosity in solving problems. It has all these rewards on its own," she said. She decided to get her doctorate in conservation biology. She faced a problem. Virtually no programs offered the kind of big-question, interdisciplinary approach she wanted. The only possibility was Stanford, which had a great interdisciplinary tradition. The biology department even had a climatologist assigned to it. But, like most graduate programs, it was reluctant to take the incestuous step of admitting its own undergraduate. She applied anyway, causing a heated debate in the department. "Ultimately we made an exception for Gretchen," recalled Ehrlich. Four years later she shared the prize for being the best graduate student in the Life Sciences Department. Back again at Stanford in 1989, Daily joined a swirl of adventurous personalities gathering and sharing ideas, coming from departments as different as ecology, law, climate science, international studies, population studies, and economics. It was a rich moment of intellectual excitement. They argued late into the night in the dreary lecture room of the biology building. Paul and Anne Ehrlich hosted dinners in their home, where Daily met visiting professors and lecturers who shared her desire to pursue the biggest questions about Earth's future. They included Cambridge University economist Partha Dasgupta, Berkeley University energy analyst John Holdren, climatologist Stephen Schneider, ecosystem ecologists Pamela Matson and Peter Vitousek, and others. Realizing that a multidisciplinary approach was necessary to understand the natural and man-made systems they wished to master, they tried to learn about each other's fields.

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In the usual academic setting it was difficult to show one's ignorance. They preferred to meet socially, over dinners with endive salads and sea bass cooked by Anne, while Paul served obscure good wine. Only with their guard down could they begin to communicate at a gut level, beyond the professional jargon and posturing. Often in science the most important ideas come from lunches, dinners, cocktail hours, and chance encounters. Cloning pioneer Ian Wilmut picked up his key idea in overhearing a competitor's conversation in an Edinburgh pub. The Ehrlichs liked to mix younger and older colleagues. They shared ownership of an airplane with the law school dean, Paul Brest, and law school or international studies professors frequently joined in the conversations about Earth's future and governments' role in shaping it. Daily was most intrigued by the economist Partha Dasgupta, who was on leave from Cambridge, England, with his wife. Originally from Dhaka, the capital of Bangladesh, he had been thinking deeply about the connections of poverty, population growth, and the environment since his student days at the London School of Economics. A former president of both the British and the European Economics Associations, Dasgupta was using his sabbatical in California to furiously pursue interdisciplinary models. Daily was amazed that he had read all of Ehrlichs and John Holdren's book, Ecoscience. Ecologists and economists rarely talked to one another unless it was to condemn each other, "The book was huge and very technical," Daily recalled. "It made me think, I haven't read any economics. Partha made me feel it's OK professionally to do this," For Dasgupta, the dinners were equally critical. As a student, in the London School of Economics library, he had searched in vain for books that explained how natural systems interacted with human economies. He turned to a catalog of publisher W. H. Freeman and Company, where he found Ecoscience. "It was absolutely fascinating to me. I was searching but did not quite know the word 'ecology' at the time," said Dasgupta, who was doing work on exploited resources like fisheries. "The book offered the beginning of a unified way of treating resource economics and environmental economics under one intellectual scheme." Here he uncovered formulations of the same problems he had been working on, in equations an economist could comprehend. When he told Ehrlich he loved the book, "it was probably the first time Ehrlich ever heard an economist saying anything good about him," Dasgupta recalled. Invited to dinner, Dasgupta put Ehrlich in touch with a Stanford neighbor, Nobel Prize-winning economist Ken

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Arrow. "They had never broken bread together, even though they'd been colleagues for years." Two lecture series were started. Leading thinkers were invited to talk to faculty from other disciplines, in much the same way Susan Greenfield put consciousness on the map in an interdisciplinary lecture series at Oxford. But more important were the dinners at the Ehrlichs', where "great natural scientists would show up, often with graduate students in tow," Dasgupta said. For her part, Daily had thought of science as people in white coats, but that changed. "The possibilities were really stimulating, even though careerwise there were a lot of disincentives to working with other disciplines. At first we didn't agree on anything, but gradually we learned the language and the assumptions of each others' disciplines. It was fun being a part of. The social dynamics played a prominent role in creating ideas." Ignited by what she heard, Daily worked on the first thesis in the biology department to analyze policy as well as biology. With the slightly grandiose title, "Interactions Between Populations and Resources," it sought to assess the ultimate carrying capacity of "life on Earth." She later published sections of it in the British Royal Society Proceedings. What is that going to accomplish? she recalled Sandra Postel asking. Thinking what to do next, she resolved to do something that would have an impact in the real world. She had come a long way from red-naped sapsuckers, but she was only beginning. 3 The interdisciplinary approach was difficult. It is one thing when a Nobel winner or senior researcher decides to switch careers or make a name as a public intellectual. It is quite another for a young postdoctoral researcher to attempt to learn more than one discipline. Stanford was the world leader in environmental economics. But given the larger difficulties of making it in any single science field, and the limited time and resources available to her, it was a little crazy. A few were calling for science to return to its humanistic Renaissance roots. Some interdisciplinary projects were pushed by

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North American and European government agencies. But it was immensely difficult to do good work in traditions that each required years of study to master, and across different departmental assumptions so ingrained as to be invisible. Academic departments existed for good reason. You did not want your English colleagues suggesting a new treatment for cancer. The distrust of interdisciplinary work was often unspoken: back-hall gossipers suggested such scholars could not make it in their own fields, they talked rather than did, they were publicity hounds who got their information secondhandI have felt that way myself. Perhaps there is a natural discomfort with being exhorted by someone not trained in your field. In science, moreover, the funding flowed down departmental lines. Being outside of a department took you "out of the money," said Ehrlich. When Harvard Medical School's Athena Andreadis derided her coming-of-age within medicine's "feudal parochialism" and "fiefdoms," she could have been speaking of any scientific field. Few in the 1980s were pursuing interdisciplinary research. "It's either feast or famine," said virologist Rita Colwell of interdisciplinary science at traditional science conferences in 1994, before becoming director of the National Science Foundation (NSF). "Either you're the keynote speaker or you're not on the program at all." Later the NSF would require its Long Term Ecological Grant recipients to include research into the social science as well as the natural science of the regions they studied. Yet Colwell's work, as well as that of others, showed how interdisciplinary the world is. Colwell was studying the resurgence of cholera and other pathogens like tuberculosis in the worldalarming epidemics because the diseases were thought to have been conquered. Cholera was increasing because of polluted water supplies, brought on by the decaying infrastructure of sanitation and health care in poor countries. To a virologist, then, research had to encompass issues of social policy and public health. Disease was interdisciplinary, even if science was not. With the economics of ecology, the small Stanford group began to develop a vocabulary and rules of measure. In economics the standard measure was marginal valuethe extra wealth produced by one more unit of labor or a commodity. At Stanford, Daily and others asked questions like: What was the marginal value of a single hectare of rainforest? To answer, ecosystems had to become a weave of processes whose workings spread through time, from forest to town, from agriculture to culture. They expanded the science to make it reach from the sun to the joblessness of the young man raised on the street who

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might rob your research van. They became makers of worlds, scientists who slipped from investment ratios to the daily routine of Third World families to the biochemistry of bees. Daily pursued her postdoctoral work with energy-resource expert John Holdren. Amidst Berkeley's leafy hills, Daily's interests widened. She coauthored papers linking climate change and food capacity, the spatial distribution of sub-alpine butterflies, and "Figs and Fun," a how-to article of sapsucker secrets. Most she coauthored with Ehrlich, and some readers noted her growing command of economics. "Paul's writing improved as a result of working with Gretchen," said Dasgupta, as the two set out to link population studies and market economics. Daily began showing the skills that made her special. From a father who joined the Army to travel abroad, she inherited a practical ability. From her upbringing she brought an international ease with several languages. From her time in an Army school, she relearned the necessity of understanding "the views of strangers, foreigners, and enemies." From Ehrlich, Daily learned how to attack the biggest questions with confidence. She also witnessed the dramatic conflicts and show business of science (Ehrlich was an NBC correspondent for many years) and the pitfalls and potential of life as a public figure. Most of all, her colleagues observed, she worked harder at collaborating than most anyone else. She traveled to Australia and New Zealand, speaking on subjects as different as biodiversity, new computer models for gauging climate change, and the effect of climate change on food production. She applied for a prestigious Winslow Heinz Postdoctoral Fellowship as well as a Pew Fellowship dedicated to the issues of the environment and humanity's future on Earth. Her younger brother in high school became interested in making business more eco-friendly. She became more confident. "I had a lot of insecurities," she said. "But they might actually have been an asset, keeping me more open to new ideas and making me strive to improve." By the early 1990s other institutes around the world were pursuing the big questions of ecosystems and human interaction. Nonprofit groups like the Santa Fe Institute in New Mexico, the Beijer Institute of the Royal Swedish Academy in Stockholm, and the International Institute for Applied Systems Analysis in Laxenburg, Austria, sprang up as the study of complex systems gained momentum, drawing on the romance of chaos theory. More researchers felt a growing sense that science must finally overcome its own divisions to grapple with the overarching issue of humanity's survival. The fate of the Earth became an acceptable question for scientific study.

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One of the most prominent such institutes was the Beijer in Sweden. Founded in 1977 by the Royal Swedish Society and reorganized in 1991 as the International Institute of Ecological Economics, it was set in the stunning Stockholm archipelago. After delicately prepared French dinners, invited fellows joined in talks about how to attack the problems of the environment. Chaired by Partha Dasgupta, the institute sponsored annual symposia on topics like poverty and environmental degradation. Gradually, out of these symposia came the hope for a new approach to ecology, a new science. The basics were clear if dauntingstatistical formulae for determining the abundance of a species through time, Keynes's models of taxation and spending, Mill on social utility, Mead on family structure. Each new set of variables, each new discipline, hid a universe of equations and assumptions, like trap doors. The vagaries of global warming provided a good example of the difficulties. If done improperly, the simplest climate forecasts spaghettied into infinite complexity. Where did one focus? It seemed frighteningly limitless. Daily was interested in the services of ecosystems, in issues of sustainability, in biodiversity, each a career in itself. By July 1992, at the age of 27, she was giving the Beijer plenary address on population extinction, an amazing recognition for such a young thinker. But to truly address the issues facing her field, she needed to be out in the field. 4 For years policymakers had grappled with the paradox that developing countries experienced the worst population explosions and ecological devastation. They used energy inefficiently and lacked the basic services necessary to build a sound social infrastructure. Why were poor families so big, the pressures of population most critical in countries least able to confront them? One reason was that many Third World societies often were also the most unequal and patriarchal. Gender inequity led to greater numbers of unwanted pregnancies, and societal inequity allowed industries to devastate the land. Research could not fully confront economic ecosystems questions without taking on issues of culture and power.

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In Costa Rica Daily found what looked like a success story. Costa Rica, a more middle-class country than its neighbors, had managed to protect its unique natural resources. Dubbed "rich coast" by Columbus, it was split by a series of volcanic mountain chains, some of the volcanoes still active. About a third of the size of Illinois, it offered researchers twelve different ecosystems. With more than a quarter of its land protected, it had twenty-four national parks, twenty-six protected areas, nine forest reserves, eight biological reserves, and seven wildlife sanctuaries. Though it covered just 0.03 percent of the world's surface, it was home to more than 5 percent of the planet's life-forms. Daily and Ehrlich began a series of field studies in the region surrounding the Las Cruces Biological Station, documenting the response of various animals to different types of human activity. "Gretchen has a talent for picking important problems," said Ehrlich, "and then sticking with them." Soon they were working with local authorities, employing and learning from townspeople, and reaching out to local researchers. By 1993 and 1994 Daily and Paul and Anne Ehrlich felt so strongly about including sociology and policy studies in ecosystem research, they began writing a book called The Stork and the Plow: The Equity Solution to the Human Dilemma. One key to escaping the population crisis, it argued, was to increase the equality of people in the world. When women are given power over their bodies, birth rates fall. When farmers in poor countries own the land they work, harvests increase. At the Beijer Institute and at Stanford, Daily talked a lot on bird walks with colleagues about the relationship between social institutions, poverty, and population. Published in 1995, the book sparked debate and controversy. It was no mere scientific treatise, but a broad historical and cultural synthesis that linked subjects as diverse as birth rates and aspects of religion, witchcraft, and homosexuality. Scientists could no longer simply look at nature, make measurements, perform tests, and announce results. They must enter a two-way relation with the people and systems they studied. As ecosystem study became more interconnected, involving human, plant, animal, geological, and climatic systems, the models became more complex. Each refinement in one field forced a refinement in the others. Daily had practiced these ideals in San Vito. She worked with local business, political, and church leaders. She listened to the women in town. "Everyone knows Gretchen," said graduate student Jennifer Hughes. Daily hired a fifteen-year-old, call him Luis, to help her identify animals and plants. He was really good at spotting butterflies,

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which she almost never could find on her own. When they hiked, he would remember the trees where they had set their butterfly traps, ninety feet above the ground. Where she would find nothing, he could point out a coiled snake or the paw print of the furry jaguarundi. He knew which wasps were harmless and which were dangerous. The money she paid him was critical for his family. Some reviewers, however, connected the book with Earlich's earlier doomsday predictions of famine and ecological crisis. The anti-environmentalist brownlash movement, which had found a voice in Ronald Reagan, made Ehrlich a favorite target. They claimed that he ignored the triumph of technology in supplementing natural processes. He also ignored the fact that when resources become scarce their prices rise, in theory, and people reallocate their spending and find ways to replace or renew resources, or do without. Ehrlich, they claimed, ignored the give-and-take of humanity's oldest complex systemthe free market. It was true that, in the twenty years since Ehrlich had published The Population Bomb, world food production had increased, contradicting one of his main arguments. Ehrlich dueled weekly with the maverick economist Julian Simon. In a famous bet, Simon offered to buy back five commodities after ten years if their prices rose. When the prices fell Ehrlich lost, paying Simon $570.07. (Later Ehrlich and Holdren recast the terms of the bet, but Simon would not take them up on it.) The rightists gloated. Even with its flaws, The Stork and the Plow and an article with John Holdren on sustainable development sparked researchers in other countries grappling with the problems they described. At the National University in Mexico ecologist Gerardo Ceballos was galvanized. "I was seeking a way for dealing with the issues we faced," he recalled. "Paul Ehrlich and Gretchen Daily were publishing important papers in the field." Ceballos was so taken he headed to Stanford on a year's sabbatical to begin a collaboration, joining them in their field studies in Costa Rica. At about that time Ceballos was picking up Daily's work, a special position called the Bing Interdisciplinary Research Scientist opened at Stanford. Funded by the chair of the Board of Trustees, Peter Bing, there were three such endowed positions, the other two belonging to Ehrlich and former Food and Drug Administration Director Donald Kennedy. Now the stakes escalated dramatically. It was the position for which Gretchen Daily had lived her life. She had already begun to build a student following, helping along those who also wanted to do science with a social impact. Because her work was

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scattered over so many fields, there was no traditional interview with a search committee. "We simply decided that we had to find a position for Gretchen at Stanford," recalled Paul Erlich. They told her the position was "an experiment," said Daily. She was elated. Sometimes, she felt, her whole career was an experiment. 5 Beginning at Stanford in the fall of 1995, she worked harder than ever. Though not required to teach, she played an important role in devising a new interdisciplinary core science curriculum. Thinking about what she was going to do with her virtually unique opportunity, she resolved to go after the biggest picture, to study, understand, and evaluate the tradeoffs between humanity's expansion and the Earth's sustaining biodiversity. She won a Pew Foundation Fellowship in Conservation and the Environment, joining in annual meetings at remote sites where researchers argued about the interaction of society and nature. A mentor from this group was the Oregon State University marine biologist Jane Lubchenco. Articulate and energetic, Lubchenco served on several federal panels and professional committees. She liked Daily's enunciation of the study of nature's services and encouraged the other Pew Fellows to pick up the idea. They could make sure policymakers had hard numbers on nature's economic services like water and air purification and food and energy production, all done at a fraction of the cost of artificial systems. Whenever new developments were discussed, politicians thought of nature "in terms of parks and reservations," she said. "We wanted to talk about nature in terms of money," In 1995 at the White Stallion Ranch in Arizona, where paintings of buffalo stampedes and buffalo hunts covered the lodge hallways, Lubchenco and economist Peter Vitousek invited about ten people to dinner outside under the desert stars. They needed to put together the work on nature's services, Vitousek suggested. All their work was too scattered. What about coauthoring a journal article? It had to have heft, to have real data. But who could pull together their input? "Gretchen was clearly the most qualified," recalled

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Lubchenco. Everyone turned to Daily. "When I did not back out fast enough," she recalled, "I was selected." Daily was selected because she had discipline and interdisciplinary knowledge. She had above all an uncommon, obsessive commitment. Once, for instance, her Costa Rica research was criticized because her traps missed the butterflies flying high above the forest canopy. Daily took a trap and redesigned it from start to finish, seeking a way to get it ninety feet up into the trees. She decided on using a slingshotting spider wire that shot up above the canopy and then came down over a tree branch. She affixed a shutter that could be closed from down below. She installed a suite of these new traps high up in the trees, She took to the nature's services project, soon realizing that a single article could not hold all they wanted to say. She suggested they turn the idea into a book. She began assigning chapters and pursuing collaborators, reaching back to many of the different people she had met in her young career. Jane Lubchenco helped her procure grants from the W. Alton Jones and Packard foundations. Lubchenco was president of the largest and most visible research organization in the United States, the American Association for the Advancement of Science. It was a profound platform from which to announce a wider effort to document the services of ecosystems. Lubchenco decided to make nature's services a keystone of the 1997 annual meeting, in Seattle, where Bill Gates was due to speak. 6 In the spring and summer of 1996 the ideas of the book were taking shape in working drafts of nineteen chapters, cowritten by thirty-two authors assembled by Daily. She brought in economist Lawrence Goulder and her friend Donald Kennedy to explain the theoretical model; Gary Nabhan and Stephen Bachman to discuss the disastrous declines in numbers of insect pollinators, which threatened many wild and crop plants; Jane Lubchenco to examine saltwater marine ecosystems services; and her old friend Sandra Postel to discuss freshwater services. She took off on a lecture tour in Japan, returning to Providence, Rhode Island, to present a paper at the

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Ecological Association of America conference. She published eight coauthored journal articles during that year. She was driving herself hard. By the time they reconvened that summer to share their chapters at a Pew meeting in Purity Springs, New Hampshire, Daily was exhausted. She had been travelling for weeks without a break. Often at Pew meetings she organized the extracurricular hikes and adventures (she had inspired Lubchenco to go rockdiving in Jamaica), but after canoeing the first midnight with the others, she returned to her room and collapsed with a fever. Unable to join in climbing Mount Washington, she lay in bed and read manuscripts. Her depression and exhaustion leaked into her language. ''If humanity is not suicidal," she wrote, "then it must begin to scientifically evaluate ecosystems services." There was nothing new about this insight, of course. Plato had described the precipitous result of overfarming in Greece in the fourth century BC: Formerly, many of the mountains were arable. The plains that were full of rich soil are now marshes. Hills that were once covered with forests and produced abundant pasture now produce only food for bees. . . . The abandoned shrines at spots where formerly there were springs attest that our description of the land is true. How save the Earth? One had to first evaluate nature's services, in the universal language of self-interestmoney. Pollinators alone were worth some $8.3 billion a year, larger than the gross national product of many countries. Daily's chapter on soil, cowritten with Pamela Matson and Peter Vitousek, showed that up to one thousand years are needed to regenerate one inch of lost topsoil. Norman Myers asserted that the value of life's genetic diversity was quite simply incalculable. The book, titled Nature's Services, appeared at the beginning of 1997 and immediately attracted attention. At Columbia University, for instance, economist Geoffrey Heal was so intrigued by the book that he and Daily began to collaborate. He offered to help her with international economics, if she could help him with conservation biology. Like her, he loved the intellectual challenge of complexity. In February, Lubchenco made nature's services the topic of her speech at the meeting of the American Association for the Advancement of Science. While Bill Gates was predicting that biotechnology and information technology would "dominate the twenty-first century," nature's services and interdisciplinary approaches were the buzz at

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the conference. If science did not step out and help shape policies on such broad issues, said Teresa Heinz of the Heinz Family Philanthropies, it risked going the way of the medieval church. When Daily, Paul Ehrlich, and Geoffrey Heal held their conference session, I had trouble finding a seat in the packed auditorium. An article by Robert Costanza making similar arguments appeared in Nature, sparking further debate. The idea had arrived. To promote these ideas, Daily traveled to New York and Washington on an unusual book tour with economist Geoffrey Heal, business consultant Michael Kleeman, and Donald Kennedy. With the tour, "Gretchen took the idea of ecosystems services and put it on the map in a big way," said Jane Lubchenco. They met with editorial boards and policymakers, finding enthusiastic audiences at Fortune and Time. Nature's Services put her in the center of most newsmagazines, including US News and World Report and Newsweek, which made her pose in a tree, bringing on an allergic reaction to tree moths. The business section of The New York Times ran a front-page piece on it, and Science ran a laudatory review of it. Nature called it a must-read "for teachers, students, scientists, and citizens at all levels of expertise." Washington Post columnist Tom Horton called it "the most important book on the environment in years, a starting point for a desperately needed new view of Earth." Reviewers considered Daily's contributions in the introduction, the coauthored chapter on soil services, and in the conclusion, precise and well-grounded economically. Some of her colleagues loved it. Heal pointed out passages in which she clearly admitted the limits of quantitative analysis, neatly laying out the problems and suggesting mathematical solutions. He called the book a "quantum move" for her. Finally, it seemed, Daily's long years of painstakingly identifying keystone species and spatial geographic computations were paying off. Some critics, however, questioned the laxity of other scholars' contributions and confusions at the center of the enterprise. Some contributors, reviewers noted, confused the economic terms "marginal" and "total" values. The total value of say, pollinators was infinitesince there was virtually no way to artificially pollinate crops to sustain a human population. But the marginal value of one species of bee, for instance, might be relatively small if another species could serve the same pollinating purpose. Other entries, such as the one on fisheries, mistook the difference between value and cost. The contribution on global warming was dubbed out of date by one reviewer.

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The articles, in short, varied in their command of economics. The accumulation of sloppy equations, mistaken vocabulary, and shaky assumptions together had the effect of "dulling the impact," Issues in Science and Technology noted. An important review in TREE (Trends in Ecology and Evolution) called it "highly inclusive, but conceptually shaky." The most fundamental criticism, however, was of the concept itself. Was it real science of the paradigm-shifting sort, or a mere "curiosity," as the TREE reviewer put it, "like nineteenth-century attempts at a perpetual-motion machine"? Some letter writers to environmental magazines assailed the authors as anthropocentric philistines stooping to putting a dollar value on nature. Science fired back that such an ivory-tower view abdicated science's role in the formation of policy. After all, the book billed itself as a start. While many of the great theorists of the past had eschewed application, many more had become actively involved in history. Galileo actively lobbied to make his telescope useful as a military tool. Einstein had proposed to Franklin Roosevelt that the Germans were building an atomic bomb based on his theory of relativity. James Watson and Francis Crick became outspoken leaders of the genomics and neuroscience revolutions their discovery of DNA spawned. "While other scientists content themselves with tiny incremental research," said Michael Kleeman, "Gretchen's after the whole enchilada." Many ideas followed from this quest. If one gave nature a value, then one could sell shares in it, have people invest in it. Could the preservation of the present systems be "privatized" so that corporations and individuals find preservation in their interest? New York City spent $600 million to improve the Catskill watershed, rather than $4 billion to build a new water-treatment facility. Merck and Costa Rica devised a controversial joint venture to mine the genes of plants and animals in the rain forest for potential pharmaceuticals. In Florida, some thirty wetland banks were created, in which government paid a premium to companies to save and protect natural aquifers and water-purifying marshes. Some policymakers were listening. Vice President Al Gore used the concept in his speech on the new information technology initiative he announced in early 1998. Columbia University's Geoffrey Heal suggested that countries market their natural areas much as a CEO might take a company public. The ideas, which had been around for a while, now gained momentum.

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<><><><><><><><><><><><> For some time Daily had wanted to use satellite imaging, a technology many other researchers were using, to make instant assessments of ecosystem health. She contacted the Costa Rican researcher Arturo Sanchez-Azofeifa. Yes, he said, with the Landsat Thematic Mapper satellite, he would tell her when farmers were cutting forest. When coffee prices rose, Costa Rica's forest suffered; when they fell, the economy faltered but ecosystem health improved. The jovial, sweetfaced Arturo Sanchez had a personal tie to their work. His grandfather and many relatives were farmers and "probably deforested as much as anybody in the region," he recalled. "This was a way to put something back." In the spring of 1998 Daily held her first fun fair for the children of San Vito, beginning an outreach effort that became critical to her research, Sanchez, who was teaching at the University of Alberta, talked about how he would use the satellites in the sky to study the forests and fields. One of the children asked if the butterflies died in their traps. Daily went out to the van and pulled out a hand-made net trap, basically a cylinder of netting over a bent coat-hanger frame, below which dangled a platform for bait. They used molasses, rum, and overripe bananas to attract the butterflies, she explained. It smelled sweet and enticing. "The butterfly goes in here," she said, patiently. "Then it eats the bait, gets a little drunk, and just rests nice and protected from predators and rain until we check the trap and release it." They had fun, but the good relations had a serious purpose. "The local people really helped for getting the real picture of what was going on," said Gerardo Ceballos. Arturo Sanchez recalled warmly the Insane Wine Contest hosted by Ehrlich at the biological station every day at five. Ehrlich would wrap boxes or bottles of wine, sometimes local pineapple wine, and sometimes a vintage winewhatever San Vito had. They would serve it with pan añejo (old bread) and make learned judgments on its qualities. Finally Ehrlich would unwrap it with a flourish, and "it might just turn out to be vinegar or something," Sanchez laughed.

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7 Tired, excited, feeling scattered more than she wanted ever to be, Daily was becoming a science star. A leading figure of the nature's services paradigm, she lectured all over the world. She gave talks in Spanish at Central American universities, served on a committee of the President's Council of Advisors on Science and Technology, and spent much of her time doing fieldwork in San Vito. She was a key participant in annual meetings at the Beijer Institute and of the Pew Fellows. She was applying for grants, winning awards like the Newsweek Century Club citation, and being called for quotes by everyone on El Niño damage, estimated to be $13 billion. In early 1999 she flew overnight to San Jose, Costa Rica's capital, waited two hours to find her missing luggage and equipment, grabbed a rental car and headed for a hotel where she had meetings with Costa Rican collaborators. Gerardo Ceballos was coming separately from Mexico City. She felt lightheaded from lack of sleep. She got stuck in San Jose's wicked morning rush hour. As she inched forward in the diesel and gas fumes, amidst the rattling farm trucks and salsablaring car radios, she caught sight of something out of the corner of her eye. A few seconds later her rear tire blew out. Sighing, she pulled over to the side of the road and got down to look underneath the car. From the car behind her a fortyish man approached her. He was dressed nicely in dark slacks and a white shirt. He asked if she needed help. Something about him made her suspicious. "Do you live around here?" she asked. "Right in that house over there." He motioned. She got out from under the car to talk to him. He helped her, but right before the job was finished, he asked her to unlock the car door to get another tool. In an instant, he snatched her nylon hip pack, tucked away between the front seats. With it, her wallet and passport, and the well-dressed man, were gonehe was whisked away by his accomplice, hiding in a car parked out of view. Idiot, she thought to herself. What was she thinking? As it turned out, the family that did live in the nearby house came out to help her. It's a new trick, the woman told her. One of the men runs in front of your back tire to lay down nails when you are stuck in traffic. "We were suspicious, but he seemed so helpful we didn't intervene," the woman said, while her son-in-law helped fix the tire. "You're lucky worse didn't happen." They reported the robbery to the local police, and learned that the owner of the get-away car was part of a wellknown Colombian crime group.

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By the time she reached the hotel a short time later, several hundred charges had already been made on her credit cards. She checked her e-mail. She had a grant deadline the week she got back. Crime was taking a turn for the worse in San Jose. Everyone had a story. People had been mugged or accosted and hustled. The bottom had fallen out of coffee prices, and with the growing influx of tourists came Colombian and other crime groups. Once a perfectly safe country, Costa Rica now offered some of the same problems they had been studying. It seemed that the arguments in The Stork and the Plow were proving themselves. On the other side of the world, fires raged in Indonesia, launched by deforestation and desperation in the failure of Asian markets. Disease and drug addiction were the scourge of Eastern Europe and Russia, driven by alcoholism, prostitution, and the decline in living standards after the fall of communism. The fear of new viruses unleashed as development pressed deeper into the African and Asian wilderness was now overshadowed by the resurrection of old viruses like tuberculosis, propelled by the collapse of government health systems. With international travel the world was ever more interdisciplinary. Daily was busier than ever. Her life was no longer her own, she sometimes felt. She was scheduled to speak at the World Economic Forum. Jane Lubchenco arranged for her to be one of the first group of Aldo Leopold Leadership Fellows, giving her intensive training in dealing with the media. She spent a great deal of time giving talks to nonscientists. No one disagreed that nature provided invaluable services to humankind, that it had to be protected, and that scientific formulations must play a leading role. The issues spun out from the concept of nature's services were becoming more and more complex. U.S. ranchers who destroyed habitats could "rebuild" them elsewhere. In biotechnology a race was on to gain rights to genes, gene pools in natural populations, and potential drugs from the natural world. The implications were staggering. Meanwhile, the ecological devastation accelerated. "An observer from outer space," Daily wrote, "would likely conclude that next to nothing was being done to arrest or reverse fundamental aspects of environmental degradation." Since 1970 over two-hundred-fifty million people, almost the population of the United States, had died of hunger. Since 1981 the total crop area of the Earth had shrunk by 5 percent. An area the size of Colorado was abandoned each year because it was no longer viable to farm.

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Yet arguments against nature's services also continued. That the doomsayers ignored the great advances of the past twenty years was the gist of an article in The Atlantic Monthly by Greg Easterbrook and, later, a more thoughtful piece by Mark Sagoff. Decrying first of all the ecologist's tendency to sound like Chicken Little, they argued that ecosystems science was full of holes. Though neither were scientists, they were good writers, and their ideas caught fire. "We don't highlight the successes as well as we should," Daily agreed. But she assailed Easterbrook's demagogic use of isolated facts to weave a pattern that's "plain wrong," she said. The Earth was losing more natural lands faster than at any time in its history. There's no value for a Brazilian rancher to keep up a hectare of rain forest. She wanted science to give them that value. Later in 1999, she learned that her assistant Luis had been falsifying data for months. She felt guilty for allowing such a young man to be so critical to the research. She had no choice but to dismiss him. But she called on others in town, like Jesus Ilama, church deacon, who fashioned guitars in his spare time. He became their star mammal trapper. Another townsman, Randi Figueroa, specialized in butterflies. Still, they had troubles. Once a major bridge was torn down to be replaced and they had to leave the car and walk several miles out of their way. Another time, recalled Jennifer Hughes, Daily asked for a shovel to work on huge mounds of dirt that had been sitting for days to be used to fill in the ruts of a road. She kept going. They were getting good results, finding that even a small amount of preserved forest, say along riverbanks or through gorges, will preserve significantly greater species diversity that would have been expected. The possibility of maximizing tradeoffs was there, if only one knew where to look. 8 Imagine a world where you could open the business section of the newspaper and see precise, intricate measurements, not of the unemployment or interest rate, but of the latest fluctuations in the nitrogen cycle or the forest recovery in a country. It is a problem of our time that we pay such close attention to the latest tipple in

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business but little to the changes in the great wealth-producing machine that is the Earth. Today, for all the enterprise of researchers, we are still doing only a little better than flying blind. This is where Daily's work is important, as an early step toward understanding how the intensification of land use can be modified to maximize the health of ecosystems. Read only history books, and it becomes easy to think of advances and breakthroughs as somehow inevitable. It would be easy to suppose right now that nature's services is an idea that must surely be catching on. More forest is cut down every year than in the twenty millennia before ours. No one could doubt that eventually Earth's resources will run out. Technology is great, but you cannot eat it. Like Susan Greenfield, Gretchen Daily stuck to her earliest interests in the humanities and turned to lectures, popular journalism, and collaborations to carry out her complex quest. Like Greenfield, she wrote frequently for the press and tirelessly grabbed every opportunity to push an agenda she believed in. This got her into trouble but it made it possible for her to work on a shoestring, as did Marcy, when the rest of science was not supporting her complex-systems approach. Like Venter, she organized science panels at major meetings, especially at the oftdenigrated AAAS meeting. The jury is still out on how much of a paradigm she is shifting. By her mid-twenties she had pushed to the front of the most challenging goal of sciencethe study of Earth's sustainability and the future of our species. "Gretchen drew in a broader range of expertise that turned out be absolutely brilliant," said Jane Lubchenco, new member of the National Academy of Sciences. "But it's too early to say how countryside biogeography will play." Sitting at the edge of the front row during her panel at the AAAS convention in Seattle, I watched her take questions on nature's services and on the resurgence of El Niño. She had the uncanny ability to talk with people from completely different fields. I was amazed at her breadth. When we met for breakfast at Stanford, she was self-deprecating when a difficult question came up, or when she was challenged on the idealism of her quest. Reporters called her to comment on every manner of climate and ecosystems disturbance. We face great scientific uncertainties, Daily wrote, "but clearly most of the action is on the social side." To play tennis well, a friend once told me, you have to play with no ego. I took that to mean, do not be afraid to fall on your face. Just get back up and play.

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Drawn to Truth: Carl Woese and the Archaean Revolution 1 In a cave in the mountains of Chiapas, in southern Mexico, thirty-five-year-old microbiologist Norman Pace dangled from a rope. Below him the cavern's river dove down a waterfall and then down a much bigger eightyfive-foot cave drop called Fool's Falls. The slippery stone smelled of earth. Leading one party in an amateur expedition to map the cave, Pace was laying a phone line to a camp a couple of hundred feet below the surface. They needed the phone because when it rained, much of the cave flooded. You wanted a phone line to check the surface weather. Otherwise you could die. Rigged onto a seat sling clipped to the line, he lowered himself into the water, bobbing, spooling out line, letting the force of the icy stream push him forward. The small, energetic Pace had been exploring caves since he was a small boy in rural Indiana. He could tell you the date, June 22, when he had first followed two guides into what seemed a routine cave in a state park. They showed him a hidden fourteen-hundred-foot crawlway, where a cool dank wind blew from an enormous, newly discovered cavern deep inside. In his life as an amateur explorer, Pace had uncovered several new caves and caves within caves. In Kentucky's Mammoth Caverns for instance, with its gift shop and tour guides, he once peered up from the main trail and, spotting a shadow, climbed up to uncover a new mile-and-a-half-long passageway. Caving was a hobby he considered critical to his science. It taught him that much of what we think we knowwe do not, really know. The

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most exciting possibilities often lay where you thought you should not be looking. "Exploring caves teaches you that if you think it's all known, you fall prey to circular reasoning," he said, "into a paradigm of self-satisfaction." Suddenly his anchor popped loose. One minute he was moored, the next minute he was dropping down into a rushing torrent toward a precipice. The rapids ripped away his glasses, the spool, his pack, everything but his light as he plummeted over the first waterfall. Halfway down, the rope above him yanked and caught. It snagged his ankle, yanking him up directly under the waterfall, hanging upside down. Icy torrents of water poured into his nostrils and mouth. He writhed, seeking a space to breathe. He was drowning. At the time, Norman Pace was an associate professor in Denver attached to the National Jewish Center. He was a leading researcher, on his way to election into the prestigious National Academy of Sciences for his work on the physical structure of RNA. But his most exciting work, what he called The Search and likened to cave exploring, had not yet begun. Shortly before Norman Pace struggled in a waterfall in a Mexican cave, a friend at the University of Illinois had come up with a discovery that shook the foundation of Darwinian science. Carl Woese, a physicist turned evolutionist who was fourteen years Pace's senior, had always felt "drawn to truth." For years he had studied the short sequences of bacterial ribosomal RNA, seeking the cellular keys to evolution. Most others were using DNA technologies to launch the human genome revolution, but Woese, working mostly alone, was studying the RNA of bacteria in a much bigger quest, for the history of life. In that search Woese stumbled across an important discovery in 1976 and 1977. Studying a little-noticed group of organisms he had found a whole new kingdom of life, a third domain that offered a new key to the origin of all life on Earth. Funded by a small NASA grant for seeking extraterrestrial life, Woese was proposing a new concept of life to the scientific world. But his ideas about the microscopic organisms he called "archaea," for the "ancient ones," were being met with ridicule and hostility. Even he did not realize their full import. It was not enough to have a good idea. He and others had to prove it, to explore and map its implications. Struggling to pull his head out of the wall of rushing water, Pace had no thought of archaea. He was fighting as hard as he could. His friends were pulling on the rope and yanking him back into the rushing torrent. He yelled but they could not hear him. He pushed with all his strength into the water, bouncing against the current into the

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air where he grabbed hold of a slippery outcropping, hands bleeding, coughing and gasping. It would take another decade or so, but together Norman Pace and the retiring Woese and others would usher in what Science called a ''new era in one of biology's grandest, if most problematic pursuits: understanding the origins of life." Woese laid the foundation, and Pace developed the technique, for uncovering a teeming universe of unknown life, leftovers from primordial Earth, in overlooked environments like the bottom of the ocean, the bubbling hot springs of Iceland or Yellowstone, the superhot minerals and rocks miles below the Earth's surface, and watery sulfuric caves. As it would turn out, these strange organisms overran almost every environment on Earth. They showed that our concept of species and kingdoms was incomplete; our tree of life was stunted; our perception of species balance in the world was myopic. "Look at the visible world with a trained eye," Woese said, "and you see microorganisms are the underpinings of everything," The normally staid journal Science called the archaean discoveries "a new paradigm for understanding life on Earth." What followed transformed fundamental and applied biology. Much of this came from a friendship between Woese, an unusual and quiet thinker working alone in an unkempt lab, and Pace, an adventurer whose near-death experience exemplified a spirit that recast the direction of a science. What put Carl Woese on the edge of the biggest acceleration in the history of microbiology? Why did his breakthrough lead others like Pace into discoveries no one had envisioned? The story of the archaea is a parable of creativity and collaboration. It is a story of years spent outside the mainstream of a field, seeking the extraordinary in the ordinary, following an idea as if your life depended on it. This is a story, ultimately, of the power of thought and friendship to uncover an unseen universe in the forgotten crannies of the world. 2 For thousands of years, our understanding of life had been divided very simply between two groups, plants and animals. With the seventeenth-century invention of the microscope, a new group was added, the microbes. There matters stood until the 1930s, when a more scientific division was offered, based on the features of

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the cell, differentiating between the bacteria, or prokaryotes, on one side and everything else, or eukaryotes, on the other. About that time, Carl Woese was growing up in Syracuse, New York. Born July 15, 1928, he was the son of a consulting engineer and a stay-at-home mother. He attended Deerfield Academy and then Amherst College, where he loved physics and mathematics. He was shy in groups; he had a slight build and an offbeat sense of humor. He liked to get to the bottom of things. "Ever since I was a kid," he once said, "I wanted not only to understand things superficially, I wanted to understand them deeply." As a graduate student at Yale he gravitated toward evolution and began pursuing biophysics, what we today would call molecular biology, which could offer, he thought, the mathematical rules that governed life. As he turned in his thesis, however, Watson and Crick were publishing their discovery of the structure of DNA. Woese felt "I wasn't good enough to be a scientist." He thought he could never match them. He switched to medicine for "two years and two days," but found it too cold-blooded. He returned to Yale for postdoctoral work. At the time biology was split between two domains, one dominantWatson and Crick's cell biologyand one subordinate, the older Darwinian study of evolution and natural history. Evolution was the nineteenth century, exemplified by Darwin's pencil sketches of dodo birds and fossils and the eccentric spirit of the Renaissance collector. Cell biology was the twentieth centurymathematical, brash, and promising to harness life as relativity had done for the atom. The two sides had little to say to each other. Within cell biology itself, the rage was to understand "translation," the complex biochemical interactions by which DNA exercised its power in the cell. Two models of translation battled for acceptance in the late 1950s. One model, proposed by the physicist George Gamow, argued that DNA interacted directly with the amino acids of the cell to create proteins. Another, suggested by Francis Crick, argued that there had to be an adapter molecule. Most of biology sided with Crick. Woese sided with Gamow. He shared the physicist's conviction that you could find the principles that underlie the processes of the world. "Physics takes a complex world and makes it simple," Woese said, half-laughing. "Biology takes a complex world and makes it more complex." It was not too much of a leap for him to side with the iconoclastic. Woese was schooled in a rich tradition of pursuing first principles. His mentor, Ernest Pollard, had worked with Chadwick, the discoverer of the neutron. Chadwick in turn had been trained by Earnest

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Rutherford, Cambridge's pioneer of atomic structure. "It was like studying American history with the Adamses," Woese said. He landed a job doing basic genetic research at, of all places, General Electric, in a short-lived corporate division. While he was there, a cellular building block called transfer RNA (tRNA) was discovered elsewhere, and biology leapt on it as Crick's "adapter" molecule. For Woese, this apparent disproof of Gamow's idea posed a crisis. Instead of abandoning his intuition, however, he decided that if the theory did not match the facts, then the facts were incomplete. If nucleic acids did not interact with amino acids in cells now, he reasoned, perhaps they had evolved from a time deep in the past when they did. "So I had to become an evolutionist," he said. With this quiet leap Woese offered to bridge the study of the cell and the study of evolution. To him this was natural. "You can't sequence the same protein in two different organisms," he said, "without starting down the path of becoming an evolutionist." In the field, though, he was trying to synthesize two completely separate disciplines. If he was right, it was a stroke of genius. He was foreseeing dynamic change in a static study of cell structure, somewhat as Newton had seen change in the static world of mathematics two centuries earlier. If he was wrong, then he was crazy. His later students would comment that in discussion he did not distinguish too heavily between great ideas and nutty ones; it was hard to tell the difference at first. Quiet and introspective, he thought instead about how he was going to prove his idea. 3 When General Electric's stock plummeted, Carl Woese had to look for a conventional university job, which he found at the University of Illinois in Urbana. Miles of feed corn and soybeans from Chicago, it might have seemed a backwater, but it was forging a stellar tradition in microbiology. The great Salvador Luria, mentor to James Watson, once taught there. Woese joined a rich group of colleagues like Ralph Wolfe and Sol Spiegelman, and they eventually formed "the best microbiology department in the country,"

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recalled a student, Dave Stahl. Urbana afforded them the freedom to think independently. "It was a place you could pursue your own ideas without interference," said Ford Doolittle, a younger postdoc who had attended Harvard and Stanford, but came to Illinois to be with Woese. Woese's lab was small. He did not waste time writing for grants and did not like to travel to a lot of conferences; he was in the lab forty hours a week, accessible to students for questions. He attracted an unusual group of "castoffs from other labs," said Mitchell Sogin, now the Director of the Woods Hole Program in Molecular Evolution. "Not that they were any less worthy, but they just didn't fit normal molds." They included people whose interests ranged more widely than straight microbiology, like Michael Bleyman, who went on to the University of North Carolina but eventually opened a breeding program to preserve the gene pools of carnivores like tigers, leopards, and jaguars, and Lee Sutton, a philosophy enthusiast who was in no hurry to finish his degree. They gravitated to and learned from Woese's broad vision of what science should be, according to David Stahl, who went on to become an award-winning microbiologist at Northwestern University. "But [science] is not often practiced that way. Carl thrived on being an outsider." They learned something else, that a career was not just about giving papers or winning the largest amounts of money. "He treats science as though it is some sort of holy temple," said Mitchell Sogin. "It almost takes on a religious tone, though not in a deity sense. He worships science. He worships truth." Seeking the secrets of evolutionary history, Woese focused on bacteria, the most ancient of life forms. To do that, he needed first a system of classification, much as Darwin had needed to classify the fossils and species he discovered in his Beagle years before attacking the question of their history. While there existed extensive family trees for animals and plants, at the time there was little for bacteria. The giants in the bacterial field, C. B. van Niel of Stanford and his student Roger Stanier of the University of California at Berkeley, had struggled in the 1930s to make such a tree. They declared it impossible to catalogue the blobs, cylinders, spheres, squiggles, and tubes that infected old cheese or dotted a microscope slide. Just a handful of soil alone contained billions of microbes. They were difficult to grow in pure culture, if too easy in your refrigerator, so biological work concentrated on the few weeds, like Escherichia coli, that could be studied in pure culture. Because what we did know was mainly about E. coli, it was then reasoned that everything else must act like E. coli. The intellectual inertia, Woese said, "was astounding."

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Woese thought that if you wanted to understand any deep evolutionary question, "to go back to where Darwin was unable to go . . . it was obvious that you needed to be able to see the relations among species. It was like going to a zoo and not being able to distinguish a zebra from a lion." Coming from physics, he did not fear taking a fresh approach. "I hadn't been trained as a microbiologist," he told Virginia Morell of Science,"so I did not have this bias." In 1965 Linus Pauling and Emile Zuckerkandl found a way to make a universal tree, sounding a "clarion call" in an article in the Journal of Theoretical Biology titled ''Molecules as Documents of Evolutionary History." They showed that molecular sequences in cells offered an organizing principle for life's family tree. Nabbing their idea, Woese focused on ribosomal RNAs (rRNA). Because the ribosome made the proteins that did the work of life, the nucleic acid that it was made of, the rRNA, could have been the most ancient of nucleic acids. RNA was also simpler and shorter than DNA, making it easier to study in those early days. It could be extracted fairly easily and was found in all organisms. "It was the bar code of an organism," Woese said, "that identifies it and at the same time relates it to other organisms." In 1966, though, few tools existed to analyze RNA. Woese had to adapt a time-consuming method, called oligonucleotide cataloguing, devised by Fred Sanger, the interdisciplinary figure who had already won one of his Nobel Prizes. Like DNA, RNA is made of four different basesadenine, cytosine, uracil, and guanine. Sanger's technique cut radioactively labeled rRNA into very short snippets, sorted the fragments by size and electric charge, and exposed them together on X-ray film. The resulting transparency showed only cryptic groupings of spots, but their arrangement gave Woese clues to the base sequence of the original rRNA. Over the years Woese began to build up hundreds of these large films into a library of bacterial rRNA, which he stored in yellow Kodak boxes in his closet. To study the transparencies he covered his office with light boxes, including one entire "luminescent wall." He became the world's leading expert on them. "He stood there all day, every day, looking at these, searching for patterns," said the University of Georgia's William Whitman. "Only three or four other people could understand what he was doing." For relief, he did chin-ups on a bar in his office and drank Dr. Pepper. In a cramped cluttered lab with its windows blacked out, he combined mind-numbing detail work with the broadest possible quest. "None of us really had an appreciation for what Carl was trying to do," recalled Mitchell Sogin. "I'm not sure he had a full appreciation for how it would work out."

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From 1966 to 1976 Woese taught his classes and slowly built up a library of about sixty bacterial rRNAs, arranging their patterns into a fledgling bacterial family tree. Other researchers were sequencing proteins toward the same goal, but the proteins were not as universal as rRNA. Woese published bacterial phylogenies in 1975 and 1976, helping to build confirming evidence that advanced cell structures such as mitochondria had actually been external bacteria captured by other cells, eons ago, and incorporated symbiotically. He gave a talk in Paris where NASA's extraterrestrial biology director, Dick Young, was in the audience. Afterward Young asked him to write a grant proposal, the only time "that has ever happened to me," Woese said. Young provided a critical early grant of $50,000. With the money, Woese solicited suggestions from colleagues for good candidates to analyze. In 1975 Ralph Wolfe suggested doing the methanogens. Little was known about these humble microbes that lived in sludge, mud, and in the intestines of cows and humansstrange environments, some of which were as caustic as sulfuric acidproducing methane gas. They needed no oxygen to survive. They were intriguing. As he studied them, he became more and more puzzled. Their rRNA looked foreign. The transparencies were missing the signatures of certain bacterial sequences. He told Wolfe that they must have run the wrong RNA. They tried the experiment again. Over the months, he built his data in little green books that only he could understand. A jazz aficionado, Woese once compared his work to listening to music. "You have to pick up on these faint tunes," he said. "And if you like them, you go to where you can hear them better." George Fox eventually coded the data on punch cards, writing an early computer program to interpret it. "You could try to help him," Fox recalled, ''but it was exhausting and he always did it himself anyway." Since the 1930s life had been divided into two kingdomsthe prokaryotes, like bacteria, whose very simple cells lacked a nucleus, and the eukaryotes, like the plants and animals, whose cells contained nuclei and developed structures and organelles. With a jolt Woese realized he was seeing something remarkable. His microbes looked like bacteria on the outside, but not on the inside. They were nothing less than an entire new kind of life, and a bridge between bacteria and everything else. At first he thought it was impossible. But as he thought, he realized the old two-kingdom model had never once been tested or verified. And it was wrong. He confronted Wolfe in the hallway outside their offices. "These aren't bacteria!" he said.

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"Of course they're bacteria," Wolfe recalled responding. "They look like bacteria." Ten years of staring at slides had taught Woese one thing: that the proof was not in a being's appearance, but in its ribosomal nucleic acids. He checked and rechecked his data, convinced he had discovered an entirely new form of life. Their primitive metabolism and extreme habitats suggested that these were very ancient organisms, perhaps at the root of all life on Earth. He needed a good name to capture the wonder his discovery inspired, He settled on "archaea" from the Greek archaios, ancient. In a last moment of self-doubt, he added "bacteria" to the end: Archaebacteria, "Arkies,'' for short. Woese called NASA to say he had an urgent announcement. NASA scheduled a press conference. It was kept a low-key affair, without even Woese present, but on November 3, 1977, Woese's discovery made the front page of newspapers around the worldThe New York Times, even his local paper. That day Woese emerged from his office to bask in the expected public attention. He stopped to order a coffee at a fast-food place in town. He approached the girl at the checkout. "Do you know me?" he asked. She smiled blankly. Then she brightened. "Oh, yeah," she said, "you're Bob's dad." The response of his colleagues was far more discouraging. Some resented the news conference held the day before the findings were published in The Proceedings of the National Academy of Sciences. "The reporters couldn't understand it," recalled Ralph Wolfe, "so Woese called it a 'third form of life.' Of course that caused a lot of confusion." Some suggested Woese had spent too much time in front of a light box. Because Woese abjured conferences and few understood how to read his transparencies, he was viewed as a crank whose methodology was suspect. He was not really a biologist. No one else was using his technique. Others said his rRNA tools could not possibly answer the questions he was asking. The reaction was all the more difficult because it was insidious. No one published a reply or attempted experimentally to refute his conclusions. Harvard's Ernst Mayr was a main opponent. The day of the press conference, MIT's Salvador Luria called Ralph Wolfe. "You're going to ruin your career," Luria said. "You've got to disassociate yourself from this nonsense!" R. G. E. Murray, editor of microbiology's definitive text, called Bergey's Manual, would include archaea only as a subfield under bacteria. Woese had hoped at least for a response from the microbiologists van Niel and Stanier. He never received one, even though Stanier did write a note of appreciation to a colleague who later applied Woese's

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technique. "I'd read Structure of Scientific Revolutions," Woese recalled, turning to Thomas Kuhn's ideas on the history of science to help survive the crisis in his career. "I knew exactly what was going on. First the field ignores a new idea, then there's ridicule, and finally comes acceptance." Only in Germany, where the celebrated microbiologist Otto Kandler immediately grasped the significance of Woese's finding, was his work given the recognition he felt it deserved. Kandler arranged for the world's first archaea conference to take place in 1981 in Munich, inaugurating an annual series. Knowing Woese's sense of persecution, Kandler arranged for a church brass choir to greet Woese as he rose to address the conference. "That was a jolly time," Woese recalled almost twenty years later. "Kandler was thoughtful, and he was open." But even after a generation had passed, Woese remained sensitive, and he held on to his anger. "Even now," Norman Pace recalled, "he sometimes lashes out at people on whose shoulders he stood who, he thinks, failed him because they didn't recognize archaea." Others remarked on the magnitude of his claim. ''It was a new idea and people struggled to accept it," said Ford Doolittle. Woese had not been looking for a new branch of life when he began his quest: he had been seeking the history of cellular evolution. He wanted to find the Universal Ancestor of all life on Earth, and he returned to that quest after announcing his discovery of archaea. Eventually he began reaping the rewards of a life of the minda MacArthur genius grant, the Leeuwenhoek Award, microbiology's highest honor, and election to the National Academy of Arts and Sciences. The three-part tree of life he developed was startling. Most life is single-celled and invisible to the naked eye, it showed, with plants, animals, and the rest of visible life only a small twig of an enormous tree. If microbiology was going to apply what he discovered, though, it would require other scientists to seek more data and expand on its implications. But no one was leaping to devote years of research to a controversial theory proposed by a cranky personality. For his part, while he was "really taken with the concept of the Big Tree," Norman Pace was looking at the physical structure of ribosomal RNA in a quest for better understanding of the cell and, eventually, things like better medicines. He was not really interested in archaea for archaea's sake. He had little desire to be "Paul to Carl's Jesus," he once said. But his friendship with Woese helped him realize that the older scientist was giving "a new sense of the space of evolution," he recalled. Pace was attuned to mapping spaces because he was attuned to map-

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ping caves. He loved exploring and caves; the Woesean tree provided a profound new map with which to look into both. 4 Growing up in rural Indiana, Norman Pace came to the University of Illinois as a graduate student in microbiology. He did not work in Carl Woese's lab, but they talked a lot. In 1969 Pace went off to the University of Colorado in Denver, where he stayed for fifteen years, rising from assistant to associate to full professor and exploring the mountains and caves around Boulder, in Mexico, and elsewhere. He ended classes and conversations with "Let's rock!" Short and scrappy, he was an ebullient teacher. Pace was captivated by the possibilities of RNA. He compared the study of its architecture to the multidimensional thought involved in mapping caves. His harrowing experience at Fool's Falls, and others in his explorations, had "shown me that not looking in the right place could be the way to discover something new," he said. Talking to Woese, he began to realize that his map of life, using RNA, was still incomplete. In the lab scientists had been able to cultivate only a fraction of the true number of microbes. "Woese provided the . . . framework of evolutionary relatedness," he said. "But still we knew absolutely nothing about microbial diversity in the world." Many people became interested in RNA as the primordial essence of life, dating back earlier than the more complex DNA. But they could not yet prove RNA was capable of reproducing itself, the sine qua non of life. In 1981, the same year as the first world archaea conference in Germany, the University of Colorado's Tom Cech found something close: RNA could splice itself. When Sydney Altman at Yale made a similar finding, suddenly evolutionists could look at early life and "contemplate an RNA world," wrote Walter Gilbert in Nature, in a famous line that gave birth to a whole field of study. Cech came down from Boulder to speak, and Pace and another Woese associate, Gary Olsen, were in the audience. "It was like, wow, this changes the world!" recalled Olsen. Around that time the deep-sea research submarine Alvin was finding enormous caches of unknown microbes living around volcanic

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vents in weird communities with giant tubeworms and other creatures. Because archaea and their microbial cousins thrived in nearboiling water, they were called extremophiles or thermophiles. Some fed on carbon dioxide, others on hydrogen sulfide. The photosynthetic types did not use chlorophyll. They were, in a word, oddballs. Pace became interested in them, however, because extremophiles had highly stable ribosomal RNA, and they could be useful as he sought to understand the physical structure of RNA. He called a researcher for some sample cells. It was 1984 and Pace was on sabbatical back at the University of Illinois. Pace waited, then wrote and called again. Time was short. Still no cells arrived. While he was waiting, Pace picked up a book by the University of Wisconsin's Tom Brock called Thermophilic Microorganisms and Life at High Temperatures. It described the thick rugs of brilliant pink filaments of hyperthermophilic bacteria living around Yellowstone's Octopus Hot Springs. Pace thought about the idea. "Hey," he burst out to his group. "Forget about waiting for cells. We're going to get a bucketful of mud and sequence everything that's in it." "But you won't know what the organism is," objected postdoc Gary Olsen. "That doesn't matter. The RNA will tell us what we've got." They all sat for a second, stunned, as the idea sunk in. They could just go out, suck up ooze along a tourist pathway, and then randomly analyze it. For a century microbiologists had driven themselves crazy trying to achieve pure cultures in a lab. "Just do it in the dirt," Pace said. They could do shotgun sequencing of genes straight from the environment. "Do you know what you just said?" Olsen asked. "You just transformed microbial biology." 5 In forgoing lab experiments on cultured micro-organisms Pace offered a new way of seeing, more akin to the reality of life than what a traditional laboratory approach revealed. Microbes did not exist in the world as designated "species" in petri dishes, they lived in teeming symbiotic communities in which they borrowed freely from

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one another's food, waste, even perhaps their genes. The non-oxygen-breathing archaea, for instance, almost always existed with organisms that did need oxygen. The seething throngs Alvin had discovered on the ocean bottom showed that symbiosis, not independence, was a paradigm for life on Earth. Pace now offered a way to take "a natural history approach to microorganisms," said David Stahl, something that Darwin and others had done for plants and animals, but never before for the invisible world. It was an assault on the whole idea of what a laboratory or a species is. It would also be fun. "The hot springs idea was like another cave to Norm," said Ford Doolittle. "It gave him an excuse to go to Yellowstone. I would have been afraid to try it." Excited, a group including Pace, Woese, David Lane, Gary Olsen, and Dave Stahl headed off to Yellowstone in a van in the summer of 1988. "It was a kind of pilgrimage," recalled Stahl. Amidst wandering tourists, they took samples from the mud around the near-boiling pool. They stored the samples on dry ice, freezing them in a metal cooler. They brought the van back to Illinois and started sequencing. In so doing they reversed Woese's approach. "Carl Woese used the organisms to identify the ribosomal RNA," Pace said. "We used the ribosomal RNA to identify the organism." What they found was perplexingfragments of new organisms, each stranger than the last. They saw hints that the diversity of life was far greater than had been uncovered in animals and plants. What Pace came to call "The Search" really took off, however, in the early 1990s when a new postdoc and a refugee from graduate school in art history, Susan Barns, joined Pace's group and came to Yellowstone seeking new sites to sample. She took an interest in an obscure pool first noticed by another postdoc named Jim Brown. The steaming nine-by-twentyseven-foot cauldron sat tucked up above the usual hiking paths, its water boiling and spilling out into lower pools. It was so unexplored it had no name, They called it Jim's Black Pool because of its most stunning characteristicits utterly black obsidian sand. High in iron and sulfur, two prerequisites for archaea and thermophiles, it seemed a great place to search. Using a more advanced sequencing method that Pace had perfected, Barns took the DNA and focused on a particular gene that was present, but different in sequence in each different microbial species. She amplified the gene, cloned it in cultures of E. coli, and then sequenced DNA from the clones to identify the different forms of this gene from the thousands of organisms sampled. By this method she found a new pair of archaea that looked like the most primitive

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organisms ever discovered, dating back perhaps 3.5 billion years and suggesting that life began in hot pools much like Yellowstone's. Then she began to find more. By the time she was finished, she had found thirty-eight new species of archaea, some more different from each other than we are from plants. A normal biologist, studying plants and animals, might make a career out of discovering one or two new species; Barns had discovered thirtyeight in one small pool. They tried to culture the new organisms in the University of Regensburg laboratory of Karl Stetter, the world's premier specialist in culturing thermophilic microorganisms, but they could not get the most exotic species to grow. By then they needed a name for the spring. The Park Service would not allow them to use a person's name. Woese, a bit of a poet, suggested the name Obsidian Pool. Once Barns had identified the astonishing diversity of archaea in the pool, Pace decided someone should look to see how diverse the bacteria might be. He had a postdoc from New Zealand, Phil Hugenholtz, do the sampling. Digging out the stromatolites, sticky rocks covered with oozing bacteria that are probably the most ancient type of living community on Earth, he found an even greater diversity of unknown bacteria in the pool than archaea. Obsidian Pool suggested that, contrary to common belief, archaea did not all dominate thermal pools. Bacteria there outnumbered archaea fifty to one. Hugenholtz eventually discovered thirteen new families of bacteria, more than doubling the known families of bacteria, all in one pool. "We've been ignorant of diversity everywhere," Barns told Carl Zimmer from Discover, "this happened to be the place where it jumped out at us." And it was only beginning. Similar discoveries of archaea, by researchers using Pace's method, extended their habitats into temperate and icy waters as well. Jed Fuhrman of the University of Southern California and Edward DeLong of the Monterrey Bay Aquarium Research Center, working independently, discovered archaea in huge numbers in the Pacific, both on the surface and deep below. The search became "an obsession of mine," said DeLong, who discovered that about 15 to 20 percent of all microbial cells in ocean waters were archaea. As for Fuhrman, based on the ocean samples he had taken, it seemed "there's a very good chance that these are the most common organisms on Earth." Even before the explosion of new discoveries, Woese decided to take a year to write a critical synthesis. In Germany and elsewhere new findings were arriving on top of each other but no one had organized and clarified the significance of the study of molecular evolution.

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Published in 1987 in Microbiological Reviews, Woese's article, titled "Bacterial Evolution," sounded quite different from any typical science review paper: "A revolution is occurring in biology;" it began, "perhaps it is better characterized as a revolution within a revolution." Recounting the history of science's mistaken models of the tree of life, Woese noted most of all how such incorrect paradigms had "stifled any real creativity." Explaining that molecules were "chronometers,'' he offered an equation for determining the exact relatedness of organisms by their gene sequences. While the article did break down the archaean and bacterial family trees, it also went further, almost to a spiritual level, about the ultimate aim of biology. Observing that physics had abandoned its old mechanistic view for a fluid, processoriented outlook, Woese argued biology must also shed its old reductionist views to explore how "processes (evolution, development, mind) somehow underlie genes, cells, brains, etc., not the reverse." Representing much of what Woese had worked on for two decades, it linked microbial diversity and evolution along with the latest findings from around the world. "It was a highly integrated article," said David Stahl, "in a way that most microbiologists had not been thinking until that point." Others might give papers or take to the airwaves; Woese thought and wrote. It worked. With three hundred citations in other journals over the next three years, his article became one of the most cited science papers of the decade. The Woesean tree was soon hanging in most every microbiology lab in the country. One person who was stunned by the article was a computer scientists at Argonne National Laboratory near Chicago, Ross Overbeek. "It was clear he was attempting something of huge significance," Overbeek recalled. "I showed the article to my partner . . . He came back and said, 'There's more science on a single page of this than you or I will do in a lifetime.'" Woese had indicated he was looking for a connection to a good computing group. Soon Overbeek would lend the power of some of the world's best computers to the quest for the Universal Ancestor. With the advent of the age of genomics, one would need far more computing power to compare whole genomes rather than just gene fragments. Woese foresaw a tremendous impact on the search for the origin of life. In 1988 he proposed to the NIH a large-scale sequencing project for microbes. The proposal was turned down. The NIH wanted to focus its resources on the human genome. Ironically, sitting on their review panel was then NIH Senior Researcher Craig Venter. It was frustrating. "The human genome is mere application; it's a drop in the bucket," Woese later said. "Here we're on the verge of a

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new paradigm to change all of biology. Microorganisms are the underpinnings of the biosphere. They are the evolutionary sources of our cells. Understanding the genomes of the microbial world is fundamental to understanding how life got to be on our planet." As for the ecological debate, "We have to understand how the biosphere works at the microbial level if we're going to be able to cope with man's stressing of it." 6 By the 1990s the U.S. Department of Energy (DOE) was ready to finance the sequencing of microbial genomes. The extremophiles had tremendous energy and industrial potential. The microbes' oils could be used in hightemperature machinery. The fact they lived off sulfur, iron, petroleum, even could absorb radiation, made them ideal as biotechnological answers to toxicwaste cleanup. Entrepreneurial companies like New England Biolabs began selling archaeal Vent and Deep Vent polymerases, used in DNA sequencing and industrial enzymes, as cleaning aids in detergents that removed pollutants like chlorine and bromine. The hyperthermophiles' resistance to heat afforded the possibility for new thermal technologies, even cancer research. At Yellowstone itself, the biomining of extremophiles became a controversial issue for the National Park Service. There was nothing new about the issue. In the 1960s, Thomas Brock of the University of Wisconsin discovered the first new microbe from a geothermal pool that he named Thermus aquaritus, or Taq. By the 1980s, Cetus Corporation was using an enzyme from Taq to speed its DNA replication by polymerase chain reaction. By the 1990s the Taq enzyme was generating $100 million a year for Hoffman-La Roche, but no royalties went to Yellowstone. The financial potential of the new organisms being discovered was staggering. The DOE was also interested in the fact that microbes produced methane by the ton, offering incredible potential as a new, clean totally renewable energy source. By 1993 the DOE was setting up a special microbial genome project with grants, to chart the genomes of these

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potentially lucrative creaturesalmost the exact proposal Woese had made five years earlier. The University of Maryland's Frank Robb arranged a meeting in 1994 at Craig Venter's world-leading genomics facility TIGR, with Woese, Pace, Overbeek, Ford Doolittle, Gary Olsen, and others, to convince Venter to join in pursuing a DOE grant for sequencing the genome of an archaean organism. Venter, of course, was mainly interested in the human genome. The idea of using his vaunted computers to understand obscure bugs was less than inspiring It was a difficult meeting of prickly egos, respecting each other but a bit wary. For years Woese had watched millions being pumped into the Human Genome Project, while the much vaster need for microbial sequencing had received very little financial backing. He wanted to go after pure science, feeling that "what we're doing here is so fundamental, that it is inevitably going to have an impact on a number of applied areas," recalled Overbeek. He suggested a variety of organisms to sequence jointly at TIGR and Urbana. But Venter, with by far the larger facility, held the cards. "Craig did not want to let the data leave his lab," recalled Hamilton Smith. After Woese gave his presentation the group headed out to lunch at a Chinese restaurant, where they loosened up over a beer. There, Venter invited Woese to serve on TIGR's scientific advisory board and agreed to a collaboration. By the time they were driving back to the airport, Robb recalled, Woese sat back and said: "Well, the motley crew did it." In the end Venter held onto the purse strings of the proposal, but formed a joint project with Woese to sequence Methanococcus jannaschii, a methanogen isolated in 1981 by John Leigh, a graduate student in Ralph Wolfe's laboratory, from sediment retrieved by Alvin from the base of a "white smoker" nearly three kilometers below the surface of the Pacific Ocean. It was named in honor of Holger Jannasch, the pioneering researcher into the deepsea microbial life. Its genome would be the third complete one ever sequenced. "It was just a tremendously exciting thing to be part of," said Overbeek. What they found with M. jannaschii in 1996 was amazing. It lived in water from 48 to 94 degrees Celsius (118 to 201 degrees Fahrenheit), under pressure the equivalent of 200 atmospheres, enough to flatten iron. It lived on carbon dioxide, nitrogen, and hydrogen. Oxygen killed it. "It's like something out of science fiction," exclaimed Venter. "Not so long ago no one would have believed you if you'd told them such organisms existed on Earth." In looking at its genes, the team led by Claire Fraser at TIGR found that 56 percent of the genes were completely

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unknown to science, unlike any found in any other creature in any branch of the tree of life. "It shows how little we know about life," said Douglas Smith, a molecular biologist at the University of California at San Diego. Some researchers even tried to connect it with the putative fossils on the Martian meteorite reported a week earlier. The strangeness of M. jannaschii tantalized everyone, but other similarly odd organisms were turning up all over the worldin Iceland, in Italy, at the bottom of the oceans, and down in the bedrock several miles below the Earth's surface. Life as we knew it, oxygen-breathing or photosynthetic, quite likely made a smaller percentage of the Earth's life than they did. Suddenly the scope of life humans had observed for thousands of years seemed woefully incomplete. With all our studies of climate, pollution, and ecology, we could know little about the future of the planet until we could unmask its underpinning, the microbes. And they held one more surprise, perhaps the biggest of all. 7 In 1998 Claire Fraser at TIGR was sequencing two new intriguing extremophilesDeinococcus radiodurans and Thermatoga maritima. D. radiodurans was fascinating because it absorbed radiation; it could have existed for eons in space on the surface of a comet before it came splashing down on Earth. But Thermatoga, a rod-shaped bacterium discovered in superhot mud in Vulcano, Italy, in 1986, provided a clue as to what came next, in the first billion years of life on Earth. "It was chosen because it is near the base of the Woesean tree," said Craig Venter. When TIGR finished with Thermatoga, researchers found something very puzzling. "A quarter of the genes are most similar to archaea," said Fraser. As other newly sequenced genomes of microbes were completed, the Woesean tree began running into problems. Computer simulations by TIGR's Karen Nelson, comparing sequences of primitive bacteria and archaea, showed there were any number of family trees that could account for the gene differences. The repetition of huge gene sequences suggested strongly that huge hunks of

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genes were freely swapped among organisms on early Earth. It made the search for the Universal Ancestor much more difficult. The idea of swapping, or lateral gene transfer, was not new. Woese had described it back in his first archaea paper in 1977, calling it "reticulate evolution" and worrying it could make for "unmanageable complexity" in building lineages. He felt gene swapping was so rampant among early organisms, one could not even think of them as individuals in distinct families. They were more like a consortium where one swallowed a neighbor's genes if they helped to insure survival. In June 1998, in the Proceedings of the National Academy of Science, Woese suggested that the heritage of the earliest microbes should not be arranged in a hierarchical tree, but in radiating branches from a single common ancestor. Some went so far as to claim that all of the planet's early bacteria came from a single giant "global superorganism." As genes became more complex, and separate species developed, it was likely that gene swapping became much less frequent. So the tree held, and the search continued. Think of the Earth four billion years ago, an infant planet. No one knows what it was like. It may have been a superhot ball of rock, rent by volcanoes and pounded by comets and asteroids. It may have had a yellow-green atmosphere with greenhouse levels of carbon dioxide, sulfur, and hydrogen. Its oceans, filled with iron and minerals and pummeled by electrical thunderstorms, could have been so hot they virtually boiled, sending up vast clouds of steam. The safest place on this vision of early Earth would have been at undersea hot vents, and deep within the rocks. There were likely no cells, no cell walls, just a soup of molecules attached to rocks or sand. Yet somehow, some time very close to the origin of the planet, organic molecules grew more and more complex, eventually forming molecules that replicate themselves, mutate. No one knows if they emerged spontaneously, a feat close to "a miracle" according to Ford Doolittle, or from organic material brought to Earth from outer space. For that matter, life could have originated in ice, where archaea also thrive. But life started early in the planet's history, and advanced rapidly. "You put a selective hammer on it and it happens fast," Pace told The New York Times. "It's shockingly fast, maybe just tens of millions of years." Three billion years ago simple cells proliferatedbacteria and archaeawith no nuclei, just genetic material and protein factories called ribosomes. They lived off hydrogen, sulfur, iron. Plagiaristic, swapping freely, "early life," in the words of Antonio Lozcano, "was

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not chaste," Yet it produced the oxygen we now breathe, the environment we are striving so hard to save. Step outside or open your refrigerator or pick up a handful of soil. You are looking at billions of unknown organisms, most of which we have never identified. Some will have biochemical and catalytic properties we can barely imagine. Some could live miles below Earth's surface, some in ice, some in boiling water. Yet they contain within their genes the history of life, of us. If they were to die out, so would we. If we were to die out, they would go on and on. Truly we are interlopers in their world. Today most every microbiology text contains Woese's three-part tree of life, though general biology high-school texts are still just catching up. The Woesean tree is "as familiar in some labs and classrooms as the double helix," reported The Scientist. Rarely has one science changed a world view so completely. Before Darwin, the purpose of natural history was to reveal the divine ordering principle. The motivation of Carl Woese when he discovered archaea was to seek out classification of microbes to answer basic questions about the evolution of life. "I was a self-taught Darwinian," he said. "But the concept transcended Darwin." What were the qualities of his creativity? He was obsessively driven, moving between the small picture and the big. He was aware of the latest findings but "purposely avoided reading in the journals," observed George Fox. "He felt it stifled his creativity." He was not too critical of himself or of others; a good idea and a crazy idea were indistinguishable at the start. He listened to others. He viewed science as a holy quest. He valued the act of pure thinking. "You have to have your own particular sensitivity to the world," Woese once said. "And there are parts of it that are beautiful to you no matter what anyone else ever thinks. You see this all the time in artists. And you see it in good scientists." There were difficulties too. Many commented on his paranoia, his worry about what others were saying about him, his feeling of never getting his due despite the enormous number of accolades bestowed on him. Yet he matched his time perfectly. By remaining independent and sticking to first principles, he opened a new way of seeing. "He had the quality of recognizing something when he saw it," said Gary Olsen. Then came the techniques of Norman Pace to reveal the incredible hidden life in the most ordinary settings, like finding hidden caves within familiar ones. Then came genomics to compare the enormous number of new genes and organisms being discovered

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Woese matched his time by thinking differently from most any other scientist, yet he used the tools everyone else was using. "Not to be too mundane about it," said Mitchell Sogin, "but Carl is just smarter than everybody else." By finding a whole new kingdom of previously unknown life, the archaean revolution should transform the study of ecosystems, energy, genetics, Earth history, of life itself, offering a new understanding of biological time and space. "What's really interesting is not what's going on now, though," Woese observed. "It's what's going to happen."

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Conclusion: Intimate Science, Big Questions We live in the age of intimate science. Susan Greenfield wants to open a restaurant in the creaky rooms of the Royal Institution. The Internet makes it possible to learn the cutting edge of a field from your bedroom, even the insider gossip and, in some cases, raw data of international projects. You can manipulate the Hubble Space Telescope from your office. Soon you may be able to buy a personal DNA analyzer. Imagine getting a few DNA sequencers. You could think of a dozen excellent, potentially lucrative experiments looking for genes associated with physical or mental prowess. Combining personal computers and the Web, you could form a company and an international collaboration. Every day would be different; every day would challenge you to try out new ideas. But these stories also hold something back. This work is gritty, daunting, complex, nearly impossible. To spot a star forty light years away, wobbling at the rate one might ride a bicycle across Grant Park, is staggeringly difficult. Perhaps it was fun, as Saul Perlmutter said of his supernovae, but there certainly are easier ways to make a living. Graduate students still worry about the sorry state of funding over their pints at Oxford's King's Arms. How were these scientists at different levels seemingly so successful? And what of their creativitywhat were the traits of this new science of synthesis, of asking big questions?

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<><><><><><><><><><><><> For clues to the practice of bold science, look first for mentors. Saul Perlmutter hung out at parties at the home of Luis Alvarez, picking up the sheer excitement and confidence of a researcher unafraid to switch fields, speak up, even look foolish. Craig Venter, by contrast, saw an example of what not to do in the lab of Nathan Kaplan, even while avidly reading the story of James Watson. Geoff Marcy had crucial quiet support from astronomy giant Allan Sandage. Gretchen Daily worked with Paul Ehrlich, learning how to promote her ideas in public while pursuing colleagues from other fields, seeking out money, and always returning phone calls from journalists. What a hoot to be a neuroscientist, the experimental psychologist Jane Mellanby told Susan Greenfield. Go, try it, Do not be afraid. Mentoring cuts both ways. It is also critical to be a good teacher to those who follow you. Many researchers teach to pay for their research, but mentoring as an open collaboration with students is also critical. Imagine the Marcy planet search without former student Paul Butler, or Marcy and Butler if they had not responded to an English freshman's e-mail. They might still be burning expensive telescope time searching useless star systems. "Teaching showed me how to think better about problems," Susan Greenfield wrote in her newspaper column, itself a forum for teaching. Craig Venter kept a lifelong friendship with his college composition teacher, Bruce Cameron, even giving him a job. Venter will also corral anyone who knows more than he does on a subject. At a conference in Australia he grilled Norman Pace on the latest findings on diversity in microbiology. Carl Pennypacker left research altogether to found the Hands-On Universe for elementary, junior, and senior high-school students. Last spring my eleven-year-old son headed to school at midnight so he could manipulate by computer the onceforbidding Mount Wilson telescope with Pennypacker's program. A science theory or experimental finding is, Einstein once wrote, a form of teaching. Mentors are critical because, in trying to follow their childhood inner drive for big questions, most of these people faced a brick wall. "There are no new questions in biology," Venter was told. He felt so let down by his rote highschool education he gave up on his mind for a while. Marcy felt so insecure on Mount Wilson he saw a therapist for depression. Daily worried what conventional researchers would think of her. Polly Matzinger and Carl Woese were at one time ridiculed in their fields. In graduate school, the universal reaction is one of self-loathing pounded in through doctoral programs on subjects from Byron to biology.

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<><><><><><><><><><><><> Having a mentor is critical, but it alone cannot account for the ways in which these people pushed their fields. After mentors, it is critical to get into a position that allows freedom of thought. In general these people did not follow conventional routes into giant laboratories. They worked outside of the main networks of their fields. Geoff Marcy taught forty hours a week for much of his career. Without a secretary in his cinder-block office when he was at San Francisco State, he often had to interrupt our conversations to take phone calls from strangers who saw his name on the Web or on CNN. "I'm sorry," he would say. "Dr. Marcy is not in." But this post allowed Marcy special intellectual freedom because no one bothered him about his research. By contrast, Perlmutter and Matzinger largely avoided teaching, surviving on grants and fellowships within unconventional government laboratories that, at least for a time, assisted them to secure the funds and instruments they needed. Still, Matzinger became a much sought international lecturer and attracted talent from all over the world to the National Institutes of Health. Venter founded his own company to pursue his ideas, as did Greenfield. Carl Woese and Gretchen Daily joined special departments at unique moments in their histories. Daily joined in Stanford dinners at the Ehrlichs' mountainside home, linking to a group that fostered independent thought. To be independent, these thinkers had to overcome the fear of looking foolish. In the moment when you feel most vulnerable, sweating and beyond your comfort zone, ideas happen. Certainly you may fall on your face, indeed often you will. But this kind of naïveté, the childlike acceptance of mistakes, is a signal that you are pushing to your limit. To do that you must also, of course, withstand criticism. Heart palpitating, Susan Greenfield first entered the Oxford pharmacology building; Geoff Marcy got out of the shower stall stuck but resolved to pursue planets. To ask big basic questions is immediately to look clumsy, to go back to the beginning. These researchers clearly pursue the biggest questions, the ones that seemed slightly unsavory in their breadth and depth. What is life, what is it made of? Where did immunity come from? What is the value of all the natural processes of a given ecosystem? To attack such questions, one must combine sweeping vision with an obsession with the specifics of a field. The intelligence is combinatory, linking three kinds of thoughtthe big interdisciplinary vision of the dreamer, the handson, bench-smart qualities of an experimenter, and the street wisdom

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of the hustler. One needs the capacity to see broadly, but to balance it by moving from the specific to the abstract and back again in ''two voices or episodes of thought," observed Peter Medawar, "imaginative and critical, which alternate and interact." At the imaginative level Craig Venter and Saul Perlmutter shared a fascination with the neuroscience and the physiology of thought well before they moved onto genomics or astronomy, respectively. Susan Greenfield loved Greek tragedy and myth, and sought in neuroscience an explanation for the truths of human existence. Marcy wanted to seek the Grail of planets in astronomy. Gretchen Daily, raised in Europe, trained in biology but immersed in economics, pursued the biggest question of allwhether we will survive as a species. This is wisdom in the intellectual sense, but more in the creative unconscious way of an artist who seeks to explain why the world is what it is. One must also get one's hands dirty. Weak as her experimental skills were at first, Greenfield learned to improve. Taking after her electrician father, she could sit down and set up an oscilloscope and show an ion buildup in a single brain cell of a rat. From there she built her early elegant experiments showing the key role of acetylcholinesterase in the brain. Perlmutter and Pennypacker lugged their equipment around the Berkeley hills, grabbed new CCDs as soon as they came out of the factory, and built a telescope from scratch. Marcy collaborator Steve Vogt built the world's best spectrograph, and Marcy cobbled together his iodine tubenow in the Smithsonian collectionin the machine shop at San Francisco State's Thompson Hall. Polly Matzinger, for all the accusations that she was only a good talker, demonstrated time and again she could conceive and execute "really important, seminal experiments" noted NIH Section Chief Ron Schwartz, in papers published in Science and Nature. When it came time to test her theory, she used her skills as sheep dog trainer to conduct her tests on, of course, sheep. The third kind of intelligence is street smarts. The remarkable thing is that none of these thinkers, save perhaps Woese, resemble anything like the solitary genius of the old mystical variety. We do not live in the age of such geniuses, it seems. We live in the age of interactive, interconnected synthesizers. Often when I checked in with Gretchen Daily or Saul Perlmutter they were on deadline to write a grant proposal. Venter pioneered commercial links to science and then took them to a controversial height no one had imagined. Greenfield founded her company Synaptica and kept the investors happy without yet showing much of a profit. Marcy's computers were eventually provided free from Sun

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Microsystems in exchange for a logo on his websiteanother source of controversy. One might worry about a space probe dotted with corporate logos, but these kinds of collaborations hearken back to the era of RCA and Thomas Alva Edison, and further. One should judge, but also acknowledge, the utility of street wisdom in finding money to make research happen today. Each one of these researchers broke down important barriers by linking their science with their inner sense of wonder. "Write what you mean to say," the writer V. S. Naipaul's father advised him. Practice the science you mean to practice, one could add, that which springs from your passions and deepest questions. To do so one has to break barriersbetween the amateur and the expert, the public and the private, and between the disciplines themselves. First, especially in astronomy, they broke the barrier of professional and amateur. An amateur, of course, loves the field. The Australian priest Robert Evans found supernovae before any academic group could. Carolyn Shoemaker, widow of planetary geologist Gene, was the first to sight the millennial comet Shoemaker-Levy 9. Anyone can become part of the search for extraterrestrial intelligence (SETI) by downloading its screen saver. Kevin Apps volunteered his time to work with the Marcy team. The breaking down of walls between professional and public extends, more importantly, to the laboratory itself. Norman Pace's revelation was that microbiologists could leave the lab and "do it in the dirt." Pace, Perlmutter, and Venter all devised ways to allow nature to do their data crunching for them. "Human DNA is the best supercomputer there is," Venter said of his EST method. The laboratory walls came down; the world in many cases became the lab. This opportunistic approach lies behind some of Daily's ideas as well; the predators of insects will count for you the number of insects in an ecosystem. One must also break the barrier with the public. That Marcy coached Little League despite not having a child on the team, and that when he coached he let the kids decide among themselves which positions to play, suggest a key trait of bold science today. Because it requires cooperation, innovation, entrepreneurship, and continually launches into new fields where one is ignorant, one must, above all, be nice. It was the best bit of advice my grandmother gave me when I got married. Just be nice, she said. The day of the science czar, the autocrat of the giant telescope or the dictator of the four-hundred-person high-energy physics team, have disappeared. There is no lack

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of ego and imperial administration in the major labs today, but for the scrappy success of these researchers, one must be nice. In his office I listened as Geoff Marcy delivered detailed, complicated directions to his house on the telephone. A former girlfriend was visiting him and Susan Kegley, he said, hanging up. Did he feel especially proud or vindicated now that he was famous?. "Oh no," he said, waving his hand. "That's just planets. This is friends." Equality also emerges from these lives. Susan Greenfield made it a point on her research team to mix ages and genders. A looser more collaborative social hierarchy was a driving force for Marcy and others who suffered under an older, more rigid science order. A powerful tool for breaking barriers is the media. All of these people have used and benefited from exposure in magazines, newspapers, radio, the Web, and television. Paul Ehrlich showed Gretchen Daily that appearing on television could be part of a seminal science career. These researchers answered phone calls and e-mails promptly, speaking articulately and enthusiastically. They moved back and forth intellectually, within and outside their groups, between their professional and public audience. Much has been written by historians of science about how ideas must be pushed into the public eye. Craig Venter made the time right for shotgun sequencing. Venter and Daily serve on several policymaking panels in Washington, D.C. Greenfield and Daily write regularly for newspapers or television. Marcy, Perlmutter, and Venter are regularly written about. Daily pens editorials and articles for newspapers and magazines. Susan Greenfield used her BBC series to check in with major thinkers in neuroscience. The relation was symbiotic. One appeared on TV because one could synthesize and explain clearly, and because one could simplify, one gained an edge as a researcher. Such clarity of vision requires a researcher to put her or his work in the tradition, communicating its meaning in history, Toward that end several read and drew ideas from popular science books. Polly Matzinger's collaborator Ephraim Fuchs got his start with Robert Wright's The Moral Animal. Venter was reading James Watson and, much later, the biography of Rosalind Franklin. Matzinger and Woese read a great deal in the philosophy of science. Once these researchers had an idea, they did not wait. If they had a motto it would be, "Do it now." When I first talked with her on the phone, Susan Greenfield wanted me to catch virtually the next plane to England. Craig Venter refused to wait another conventional ten years to sequence a single gene, having done it once. Saul Perlmutter wanted

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to pursue supernovae when everyone else thought he should wait for new equipment. When you move fast, you create your own luck. A second motto would be, "Do it with what you have." Venters paradigm shift was that gene sequencing tools available to anyone in the early 1990s were perfectly adequate for full-scale genomes, if one changed the approachfrom single genes to shotgun sequencing of the whole genome and taking what you got. Greenfield wanted to check the venom of Latin American snakes; she found a postdoc who could do it and got him some money. Gretchen Daily never listened to those who argued we lacked the tools for the sophisticated measurements of biodiversity she needed; she settled for keystone species, designed her own instruments, rolled up her sleeves, and walked into the back plots and hedgerows of San Vito. Geoff Marcy, lacking the tools for finding Saturn-size planets, said there must be a good chance planets Jupiter-size or larger exist. He went looking, and found them. To pursue their dreams speedily, each of these researchers practiced a science of new connections. First it was the mental connectionfrom precise to general, everyday to abstract. Next, it was a technological connection. To make shotgun gene sequencing work, Venter had to connect the personal computer with the remote sensing of automated sequencers, much as Daily began to use remote sensors on satellites to connect with researchers slogging through fields in Costa Rica. Perlmutter connected the new technology of charge-coupled devices with multiple telescopes around the world to find more supernovae in one night that had been observed in the previous thirty-five years. When Kevin Apps e-mailed him from England, Marcy connected with a European Space Agency satellite to pinpoint the stars he would search. In these prosaic ways the oft-trumpeted information revolution actually surpassed the claims made by its supporters, assisting innovative connections among thinkers. The new connections, more importantly, come in the form of adopting techniques from one discipline to another. Venter moved from neuroscience to biomimicry to genetics; Marcy used chemistry and astronomy to rewrite planetary science. Woese moved from physics to biology, Perlmutter from physics to cosmology. Matzinger was never accepted by immunologists, but simply went over their heads, using the media to reach out to other professional and public audiences. Greenfield moved from electrophysiology to genomics in her pursuit of neurotransmission Daily was the most obviously interdisciplinarycombining economics, climatology, botany, and ecology tirelessly with other international researchers to unlock the future of our world. "Interdisciplinary connections are now absolutely fundamental,"

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National Science Foundation Director Rita Colwell told a research workshop in September, 1998. "They are the synapses in this new capability to look . . . beyond the horizon. The interfaces of the sciences are where the new excitement will be most intense." These researchers often eschew the usual rounds of small talk, meetings, and conferences. They are consummate battlers. When attacked, Polly Matzinger went over the heads of her critics. Craig Venter framed and photographed his rejections and nemeses. Carl Woese and some members of Perlmutter's team would not keep quiet about the injustices they needed to remedy. Some of these people frustrated and enraged me at times. Polly Matzinger would sound so like an actress I would not know how much to believe. Venter could vacillate between kindness and abrupt suspicion. Carl Woese was famously moody. They were sometimes charged with going out to the edge of the verifiable in their claims and defying their colleagues. There is a definite line in science, explained Ron Schwartz at the NIH, that "separates us from our origins in sorcery." Some of these researchers walked very close to it. This is the nature of bold science. It was why some colleagues disliked Matzinger so much. But your weaknesses are also your strengths, TIGR's Bruce Cameron said. Craig Venter overextended in order to push himself and others. Greenfield set nearly impossible deadlines. Would Synaptica's investors get their money back? I asked her. "Maybe," she said. "That's what investment capital is all about.'' Finally, they share a sense of humor, seeing their work as a kind of game. "Nobody realizes how much fun this is." said Saul Perlmutter. It is fun to watch their research in Hawaii, or in San Francisco, in San Vito or in the Thames valley. If not experimenting they are either teaching, or giving conference papers, meeting with friends, going out to dinner, traveling, and mainly talking about questions like the history of the universe or the kinds of planets that might harbor life outside our solar system. Many historians and philosophers have stressed many of these traits of creative science. Now, in a digital age when so much has been written about the explosion of information, synthesisinterconnecting disparate pieces of informationhas become the single most important creative skill. Insight can come from a variety of approaches, but today it most often stems from new connections. These can happen by inspiration and mistake, as when Kekule discovered the benzene ring in a dream of a snake eating itself. Synthesis, or complex-systems science, is most like art. "Innovative science is closer to composing

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music or painting on a canvas than most people realize," Geoff Marcy said in his office. E. O. Wilson, in his book Consilience: The Unity of Knowledge, described the coming convergence of art and science. "This is where the edge of science really is," he once told me. "Art is the ultimate sythesizer." Several of these researchers were amateur artists and all were effective communicators. Marcy played cello, Matzinger piano, and Perlmutter violaall of them actively, Woese listened intently to jazz. When bringing their ideas to the public, these thinkers found the right metaphor to simplify and explain. One of the best was Polly Matzinger, whose danger model seemed glib to her critics, but brilliant to her growing number of supporters. "I can't think of another scientist who has been more influential . . . ," researcher Allan Kirk said. "She has a wonderful ability to hold down your nose in the data and make you see what is really there, recognizing as obvious [what] I had not even noticed before." In 1817 Samuel Taylor Coleridge wrote that imagination "reveals itself in the balance or reconciliation of opposite or discordant qualities: of sameness, with difference; of the general, with the concrete; of the idea, with the image; of the individual, with the representative." This combination marks the ability to intuit, a common theme among these thinkers. "I look for relationships among fields," says Craig Venter. Intuition is the best computer because it unconsciously weighs and values a huge number of variables before following a half-formed insight. These are the traits of these creative research teams as we move from what Michio Kaku calls three centuries of discovery to an age of mastery, from being observers of nature's dance to becoming its "active choreographers." These traits are not new. Most science is usually haphazard, creative, accidental. These same qualitiesof moving fast, thinking big, having a mentor, combining tools to create a synergy of increased observing powerhave been a part of creativity since the time of Archimedes. It is possible they exist on some second level of pure existence much as Plato wrote, outside of us on our dusty planet, outside of time. What has changed clearly are the tools. Today's toolsthe computer, remote sensors, artificial intelligence, automated DNA sequencers, telescopes, transgenic mice, magnetic and radiation imaging of the mindcan be combined to create a synergy of effect. These tools enable the thinker to move faster and delve deeper into questions than ever before. It is no longer an overwhelming leap to try to use the interplay of climate, nature, and economics to plot the future of

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species on Earth, or to break down the million biochemical steps that lead to a thought. By linking such tools, researchers are uncovering the processes of the universe in a new science of fluid, dynamically changing relationships commonly called complex-systems science. Such tools create a space for interactive research that privileges those who are, first of all, good at working with others and open to young ideasas Marcy showed by welcoming Kevin Apps, or Venter in working with Mark Adams, or Matzinger with Ephraim Fuchs. The current technology supports those who are open. It privileges those who can adapt to change and move fast, like Susan Greenfield. It privileges those, like these thinkers, who use the media effectively to advance their aims. You must be able to proceed, in a dark time, until the eye begins to see. It seems, these stories attest, that as dark a time as ours is, is is also a joyous time for living a life of wonder.

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Index A ABI 370, 26 ABI 3700, 26 Aborigines, 21 accelerated intelligence, 2 acceleration, 116 acetylcholine, 32, 35 36 acetylcholinesterase, 32, 35 38, 40, 45 48, 51, 172 acetylcholinesterase inhibitor, 46 acid rain, 126 127 actin, 17 Adams, Mark, 17, 18, 28, 29, 178 adapter molecule, 150 151 adenine, 153 Adler, Reid, 18 Affymetrix, 25 Affymetrix Gene Chip, 25 aging process, 19 AIDS, 19, 28 alchemy, 33, 95 alcoholism, 144 Aldo Leopold Leadership Fellows, 144 algal blooms, 126 Alpan, Oral, 100 Altman, Sydney, 157 Alvarez, Luis, 103, 104, 105, 108, 109, 111, 120, 121, 170 Alvarez, Walter, 105 Alvin, 157, 159, 163

Alzheimer's disease, 28, 39, 45 46 American Association for the Advancement of Science (AAAS), 27, 77, 95, 138 139, 146 American Association of Immunology Conference, 97 American Association of Inventors, 19 American Astronomical Society (AAS), 67, 115, 116 American Birds, 128 Amgen, 22 Amherst College, 150 amino acids, 150 151 Amish families, 19 Andreadis, Athena, 132 Andromedae, 77 Anglo-Australian Telescope, 69 70, 109 animal behavior, 46, 51 Annual Review of Immunology, 93, 98 anti-AIDS drugs, 94 antibiotics, 40 antibodies, 86, 98 Antigenics, 99 antigens, 86 87, 89 92 "antigravity force," 117, 119 API 3700, 26, 27 apoptosis, 91 Apple Computers, 13 applied biology, 149 Applied Biosystems, 15 "Approaching the Asymptote? Evolution and Revolution in Immunology," 92 Apps, Kevin, 72 76, 173, 175, 178 Arabic, 2 archaea, 23, 148 149, 155 157, 158 160, 164 166 species of, 160 archaean, 149, 163, 167

Archimedes, 177 Argonne National Laboratory, 161

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Aristarchus, 95 Aristotle, 119, 126 Arizona, 112, 115 Arrow, Ken, 131 artificial intelligence, 2, 41, 80 artificial organs, 81 asteroid, 75, 105, 112, 165 astrology, 33 astronomy, 4 Atkins, Peter, 39 41, 43, 49, 51 52 Atlantic Monthly, The, 145 atom, 3, 150 atom bomb, 3 autoimmune diseases, 80 81, 86, 90 lupus, 80 multiple sclerosis, 80 rheumatoid arthritis, 80 Type I diabetes, 80, 97 B B cells, 86 Baars, Bernard, 42 Bacchae, The, 34, 49 Bachman, Stephen, 138 bacteria, 90, 148, 150, 152, 154 155, 160, 164 165 bacterial cloning, 80 bacterial family tree, 154 bacterial phylogenies, 154 bacterial products, 92 bacterial ribosomal RNA, 148, 153 bacterial sequences, 154

"Bacterial Evolution," 161 Barns, Susan, 159 160 Basal Institute for Immunology, 88 Basri, Gibor, 61, 68 Baylor University, 128 H.M.S. Beagle, 152 beetles, 124 Beijer Institute of the Royal Swedish Academy, Stockholm, 133 135, 143 Beijer plenay, 134 Belkin, Lisa, 10 Bergey's Manual, 155 Berkeley cyclotron, 105 Big Bang, 113, 118 "big pharma," 22 Bing Interdisciplinary Research Scientist, 136 Bio '98, 27 biochemical interactions, 150 biochemical properties, 166 biochemical systems, 33 biochemistry, 13, 98 biodiversity, 125, 133 biologists, 126 biology, 68, 125 biomimicry, 30 biophysics, 150 biosphere, 162 biotechnology, 5 biowarfare, 25 birds, 124 Black Forest, 127 Bleyman, Michael, 152 Blumberg, Neal, 95, 99 100

botanists, 126 Brahms, Johannes, 64 brain receptor gene, 13 brains, 161 BRCA1 gene, 22 breast cancer, 22 Brest, Paul, 130 Brief History of Time, A, 44 British Broadcasting Company (BBC), 49, 51 52, 82, 85, 91, 95, 174 British Economics Association, 130 Brock, Tom, 158, 162; see also Thermophilic Microorganisms and Life at High Temperatures bromine, 162 Brown, Jim, 159 brown dwarf star, 67 Brown Sugar, 44 Bruno, Giordano, 58, 62 Buckingham Palace, 49 Building 4, 89 Bunny 82, 84, 87, 88 Burnet, Macfarlane, 80, 95 Business Week, 94 Butler, Paul, 62 67, 69 77, 170 butterflies, 124 C Cable News Network (CNN), 71 California Institute of Technology (Caltech), 15 Callisto, 58

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Cambridge University, 88, 129, 151 Cameron, Bruce, 11, 30, 170, 176 Cameroon, 63 Campbell, Bruce, 62 Canada, 64 Canary Island, 109 112, 115, 124 Cancer, 19, 28, 86 cancerous tumors, 80 81 carbon dioxide, 158, 163, 165 carbon, 107 Carnegie Institution, 55 56, 61 Postdoctoral Fellowships, 55 Carraway, Nick, 87 Carson, Rachel, 126 Silent Spring, 126 Carvey, Dana, 24 Case Western Reserve University, 82, 92, 99 "Castle, The," 103 catalytic properties, 166 Caucasians, 21 Ceballos, Gerardo, 136, 142 143 Cech, Tom, 157 Celera, 8, 25 29 cell biology, 80, 150 cell death molecular researchers, 91 cells, 150, 161, 165 cell structure, 151 cell walls, 165 cellular evolution, 156 cellular immunologist, 89

cellular keys, 148 cellular systems, 89 Center for Astrophysics, 116 Center for Molecular Biology, 98 Cerro Telolo, 111 Cetus Corporation, 162 CFA, 77 Chadwick, James, 150 Chalmers, David, 48 chaos theory, 133 charge-coupled detectors (CCDs), 109, 172, 175 chemistry, 67 68, 76, 125 Chile, 111, 112, 115 chlorine, 162 chlorophyll, 158 cholera, 132 cholinesterase, 51 Chubb, Ian, 36 Church of England, 34 Church of Scientology, 82 class III giants, 74 classification, 152 Cliff's Notes, 16 climate systems, 3 climatology, 126 Clinton, Bill, 9, 25 Clinton, Hillary, 9 cloning, 130 Cohn, Mel, 85 87, 100 Cold Spring Harbor Conference, 88, 92 Cold Spring Harbor Laboratory, 19, 27, 87 Coleridge, Samuel Taylor, 177

Colgate, Sterling, 106, 107 Collins, Francis, 4, 14, 26 Columbia University, 139 Columbus, Christopher, 135 Colwell, Rita, 132, 176 comets, 165 Compaq, 27 comparative genomics, 45 complex atoms, 107 complex diseases, 28 complex-systems science, 2 3, 17, 30, 34, 39, 42, 52, 74, 81, 176, 178 interdisciplinary science, 81 complementary DNA (cDNA), 16, 17 Congress, 15, 18 consciousness, 32, 39 44, 48, 52 conservation biology, 123, 129, 139 Consilience: The Unity of Knowledge, 29, 177 Contact, 66 Copernicus, Nicholas, 95, 99 cosmology, 2, 67, 106 Costa Rica, 123, 135, 141 Costanza, Robert, 140 Cox, David, 22 Crick, Francis, 10, 11, 24, 30, 141, 150 151 culture, 152, 160 cystic fibrosis, 14, 24, 28 cytosine, 153

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D Dachau, 83 dacnis, 123 Daily, Gretchen, 4, 95, 123, 127 146, 170 175 Dale, Henry, 35 36, 51 DalGleish, Gus, 97 danger, 94, 96, 98 99 danger model, 85, 177 "danger theory," 93 94, 100 dark matter, 119 Darwin, Charles, 3, 91, 100, 150, 152 153, 159, 166 Darwinian, 150, 166 Dasgupta, Partha, 129 130, 133 134 Dawkins, Richard, 43, 91 theory of evolution, 91 de rigur disquisitions, 42 deceleration, 106 deceptive mimicry, 85 Deep Vent polymerases, 162 Deerfield Academy, 150 deforestation, 144 Deimos, 58 DeLong, Edward, 160 democratic science, 14 dendrites, 37 dendritic cell, 88, 90, 92, 94 Dennett, Daniel, 41, 48 Department of Energy, 110, 112 depression, 24 Hands-On Universe program, 112

diabetes, 28 Diabetes Research Institute, 97 Diablo Mountains, 59 Diamond, Marion, 104 Discover, 22, 160 Discovery Channel, 45 diseased cells, 90 DNA, 1 3, 16, 20, 26, 30, 141, 148, 150, 153, 157, 159, 162, 169, 173 automated DNA sequencing, 28 "base pairs," 13 brains, 17 chromosomes, 13 cloning; see Shotgun DNA cloning complementary DNA (cDNA), 16, 17 "copying mechanism," 11 double helix, 3, 10, 30 genetic sequence, 2, 14 genome map, 14 junk DNA, 16, 28 library, 27 messenger ribonucleic acid (mRNA), 13 patents; see Patents replication, 162 ribosomes, 13 testis, 17 DNA sequencers, 15, 25, 26, 169 API 3700, 26, 27 ABI 3700, 26 370s, 26 Doolittle, Ford, 152, 156, 159, 163, 165 dopamine, 37 Doppler effect, 61, 107

Dostoyevski, Fyodor, 51 drug addiction, 144 Duffy, 84 Dulles Airport, 16, 26 Duracell, 72 73 Dutton, Richard, 85 dwarfs, 62 E E. coli, 21 Earth, 66 Earth history, 167 Easterbrook, Greg, 145 eccentric orbit, 67 Ecological Association of America conference, 139 ecology, 123, 125, 126, 130, 132, 134 economic ecosystems, 134 economics, 125 economists, 130 Ecoscience, 130 ecosystem, 2, 4, 124, 125, 128, 132, 134 135, 138 139, 142, 145, 146, 167 ecosystem ecologist, 129 Edison, Thomas, 22, 23, 24, 173 Ehrlich, Anne, 127, 129 131, 135 Ehrlich, Paul, 125, 127 133, 135 137, 140, 142, 170 171,

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174; see also The Stork and the Plow: The Equity Solution to the Human Dilemma Einstein, Albert, 3, 79, 100, 114, 118, 119, 141, 170 El Nino, 143 electrochemical impulses, 42 electrophysiology, 33, 36, 46, 51 Eli Lilly, 22 Eliot, T.S., 53 "Little Gidding," 53 Elle, 95 Emmett, Steve, 43, 46 49 Emotional Brain, The, 48 energy, 167 engineered life, 2 Enlightenment, 9 environmental degradation, 134 environmental economics, 131 enzyme, 162 Escherichia coli (E. coli), 152, 159 Eskimos, 21 EST method, 173 eukaryotes, 150, 154 Euripedes, 34, 42 Europa, 58 European Economics Association, 130 European Space Agency, 113, 175 Evans, Robert, 107, 108, 173 evolution, 148, 150 evolutionary biology, 80 evolutionary history, 152 evolutionist, 151

expansion rate, 106 Explorer, 76 Expressed Sequence Tags (ESTs), 17 19, 20, 29 external bacteria, 154 extra-solar planetary exploration, 76 extra-solar planetary search, 74 extra-solar planets, 57, 59, 62, 65, 69, 75 77 extra-solar system, 4, 77 extraterrestrial, 148 extraterrestrial intelligence, 64 extremophiles, 158, 162, 164 Deinococcus radiodurans (d. radiodurans), 164 Thermatoga maritima, 164 F Faraday, Michael, 43 fasciculin, 47 Fermi lab, 119, 122 Fermi National Accelerator Laboratory, 118 Fetal development, 45 Feynman, Richard, 90 51 Pegasus (51 Peg), 65 66, 70 71 Figueroa, Randi, 145 Filippenko, Alexei, 111, 113, 117, 120 First Three Minutes, The, 107 Fischer, Debra, 69 71, 76 77 Fitzgerald, F. Scott, 87 Florey Howard Walter, 40, 51 Fodor, Stephen, 25 Food and Drug Administration, 136 forest recovery, 145 Forster, E. M., 60 Fortune, 140

47 Ursae Majoris, 67 fossils, 152, 164 Foster, Jodie, 66 Fowles, John, 53; see also Magus, The Fox, Cynthia, 95 Fox, George, 154, 166 Franklin, Rosalind, 10, 29, 174 Fraser, Claire, 8, 12, 20, 163 164 Freeman, W. H., 130 French Society for Immunology, 96 Fuchs, Ephraim, 81, 89 91, 93 95, 101, 174, 178 Fuhrman, Jed, 160 G Galileo Galilei,, 3, 25, 41, 58, 62, 74, 121, 141 Gamow, George, 150 151 Ganymede, 58 Garth, 24 gene, 1, 159 gene cloning, 80 gene function, 28 gene indexing, 16, 27 gene pools, 152 gene sequences, 161, 164 gene therapy, 80 General Electric, 23, 24, 151 genes, 3, 159, 161, 166 genetic identity, 4

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genetics, 2, 4, 13, 23, 27, 28, 167 genetic material, 165 genetic research, 151 genetic sequence, 2, 14 genome investment, 27 genome sequences, 21 genomes, 8, 20, 21, 24, 25, 81, 161 162, 163 genomics revolution, 8, 9, 17, 20, 27 multidisciplinary systems approach, 25 genomics, 1, 24, 26, 46, 48, 51, 108, 141, 161, 166 geology, 68, 76, 127 Georgetown Hilton, 116 Gilbert, Walter, 157 Gillette, 73 Glanz, James, 117 Gliese 876, 75 global neurons, 45 gnatcatcher, 123 Gocayne, Jeannine, 15, 28 Goldberg, Rube, 104, 111 Goldhaber, Gerson, 109, 113, 114, 121 Goldin, Dan, 76 Golgi, Nicolai, 33 Gore, Al, 25 Goulder, Lawrence, 138 Grabar Lecture, 96 grafts, 80 Granville, Evelyn Boyd, 129 Gray, David, 70 71 green mamba, 47

Greenfield, Susan, 4, 31, 32, 34 52, 83, 95 96, 131, 146, 169, 171 172, 174 176, 178 guanine, 153 Guth, Alan, 113, 120 H Haemophilus influenzae, 20, 21, 29 Hale, George Ellery, 55 hallucinogens, 14 Hamlet, 68 Hands-On Universe program, 112, 170 Harlan, David, 97 Harvard University, 60, 64, 104, 107, 108, 112, 118, 152, 155 Center for Astrophysics, 64, 77 Harvard Medical School, 132 Harvard-Smithsonian Center for Astrophysics, 118 Harvard-Smithsonian group, 67 Harvard University Press, 77 Haseltine, William, 19, 22, 23 Hawking, Stephen, 44 45; see also Brief History of Time, A Heal, Geoffrey 139 141 Heal, Joanna, 99 heart disease, 28 heart transplant, 86 "heat shock," 98 heat-shock proteins, 98 Heinlein, Robert, 62 Heinz, Teresa, 140 Heinz Family Philanthropies, 140 heliocentric solar system, 99 heliocentric universe, 95 Heraclitus, 90 high-energy physics, 3, 104 High Resolution Spectrometer (High Res), 64, 69

High Z (Supernova Project), 113, 117 Hipparcos, 72 74 Hipparcos CD Rom, 72 74 histocompatibility complex, 93 Hoffman-LaRoche, 162 Holdren, John, 129, 133, 136 Holland, Lynn, 26 Hood, Leroy, 15, 25, 26, 28 Hook, Isobel, 111, 112, 115 Hubble, Edwin, 55, 106, 118, 169 Hubble constant, 120 Hubble Space Telescope, 110, 115 116 Hugenholtz, Phil, 160 Hughes, Jennifer, 123, 135 Hull, David, 100 human genes, 18 human genetic code, 8 human genome, 15, 17, 18, 26, 27, 163 consensus human genome, 27 Human Genome Project, 9, 15, 18, 19, 26, 163 Human Genome Research Institute (HGRI), 14

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human genome revolution, 148 Human Genome Sciences (HGS), 19, 22 24 human genome sequence, 28 human immune system, 91 human-altered habitat, 124 Hunkapiller, Mike, 25, 26 Hurley, Susan, 39 Hybritech, 22 hydrogen, 163, 165 hydrogen fluoride, 62 hydrogen sulfide, 158 hyperactive children, 42 hyperthermophiles, 162 hypothermophilic bacteria, 158 I I Heard It Through the Grapevine, 44 Iceland, 149 Ida, Shigeru, 75 Ilama, Jesus, 145 imaging experiments, 52 immune response, 88 immune suppressing drugs, 80, 97 immune system, 80 82, 85 86, 89, 91, 97 immunobiology, 87 immunological societies, 96 immunologists, 81 immunology, 79 82, 86 87 Independent, The, 43, 75 industrial enzymes, 162 inhibitors, 47

innate immunity, 94 inorganic chemistry, 35 Insane Wine Contest, 142 Institute for Human Gene Therapy, 95 insulin, 18, 22 interdisciplinary science, 81 interferometer, 64, 76 International Conference on Heat-Shock Proteins, 99 International Immunology Conference (San Francisco, 1995), 98 International Institute for Applied Systems Analysis (Laxenburg, Austria), 133 International Institute of Ecological Economics, 134 Internet, 2, 17, 69, 74, 109, 112, 113, 115, 120, 169 Intracel, 99 invaders, 80, 86 Io, 58 iodine, 63 iridium, 105 iron, 159, 162, 165 isotopes, 105 Issues in Science and Technology, 141 J Janeway, Sr., Charles, 87 Janeway Charles, 87, 90, 92, 94 96, 99; see also "Approaching the Asymptote? Evolution and Revolution in Immunology" Jannasch, Holger, 163 Jews, 21 John Curtin School of Medical Research, 90 Johns Hopkins University 20, 83, 94 Johnson, Lyndon, 10 Johnson, Magic, 62 Jones, W. Alton, 138 Journal of Immunology, 99 Journal of Theoretical Biology, 153

"Molecules as Documents of Evolutionary History," 153 Journey to the Center of the Earth, 110 Journey to the Center of the Mind, 42 Jovian, 58 Jupiter, 58, 61, 63, 65 68, 70, 175 K Kaku, Michio, 3, 177 Kandler, Otto, 156 Kaplan, Nathan, 12, 30, 170 Keck Observatory 64, 69 71, 73 74, 105, 110, 111, 112, 114, 115 Keck Telescope, 69, 75 Visitors Center, 73, 75 Kegley, Susan, 64, 69 70, 72, 174 Kekule, 176 Kennedy Donald, 136, 138, 140 Kepler, Johannes, 58, 62 Kerlavage, Tony, 13, 14, 16, 17, 25, 27, 29 Kerouac, Jack, 44 Keynes, 134 models of taxation and spending, 134

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Kikuyu, 21 King's Arms, 39, 169 Kirk, Allan, 97, 99, 177 Kirshner, Robert, 108, 110, 113, 117, 118, 120 Kleeman, Michael, 140 141 Koch, Christof, 49 Koestler, Arthur, 82, 90 Kolb, Rocky, 117, 120 Koppel, Ted, 65 Kuhn, Thomas, 82, 90, 95, 156 L Lacey, Michael, 46 Lafferty, Kevin, 86, 90 91 lambda, 114 Lancet, The, 99 Landsat Thematic Mapper satellite, 142 Lane, David, 159 Las Cruces Biological Station, 135 lateral gene transfer, 165 Lauer, Todd, 59 60 Lawrence Berkeley Lab (LBL), 104, 106, 108, 109, 110, 120 Learning Channel, The, 45 LeDoux, Joseph, 48 Leeuwenhoek Award, 156 Lehmann, Paul, 82, 99 Leigh, John, 163 Lemon, Veronica, 34, 49 Leuschner Observatory, 108 Lick, James, 59 Lick Observatory, 59, 61, 63, 65 66, 69 70

Lin, Douglas, 75 76 Lincoln College, 39 40, 43, 52 Linn, Nuna, 77 Linux, 25 Lipmann, Fritz Albert, 12 Little Mars, 68 Live, 79 Llinas, Rodolfo, 37 39, 41, 44 London School of Economics, 90, 130 London Zoo, 47 Long Term Ecological Grant, 132 Los Alamos, 106, 107 ''Lost in Space," 58 Lotze, Michael, 97 Lowe, Sandie, 49 52 Lozcano, Antonio, 165 Lubchenco, Jane, 137 140, 144, 146 Luis, 135, 145 Luria, Salvador, 151, 155 Lyme disease, 21 lymph nodes, 88 M MacArthur genius grant, 156 Magdalen Bridge, 34 Magdalen College (Oxford), 37 magnetic fields, 56 magnetic stars, 56 Magus, The, 53 main sequence stars, 74 Malthus, Thomas, 126 mammals, 124 Mammoth Caverns in Kentucky, 147

"Managing Massive Data Sets in Mathematics, Science, and Technology," 27 Marcy, Geoffrey 4, 55 77, 95, 146, 170 175, 177 marginal value, 140 Marincola, Francesco, 98 Mars, 57 58, 67, 76 Mars Pathfinder, 45, 76 Martian meteorite, 164 Massachusetts Institute of Technology (MIT), 41, 71, 113, 120, 155 Matson, Pamela, 129, 139 Matzinger, Polly 4, 79 101, 170 172, 174 178 Mauna Kea, 73 Mauna Kea peak, 104 Mayes, Vivienne Malone, 129 Mayor, Michel, 65 68, 72, 76 Mayr, Ernst, 155 McClintock, Barbara, 50 McNeil-Lehrer News Hour, 68, 117 M. D. Anderson Center (Houston), 99 Mead, 134 family structure, 134 Medawar, Peter, 80, 83, 85 86, 94 95, 97, 172 Advice to a Young Scientist, 85, 97 The Art of the Soluble, 85

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"Medicean stars," 41 Medicis, 71 melanoma, 97, 99 Mellanby, Jane, 31, 35, 50, 170 "meme," 91 Memorial Sloan Kettering Medical Center, 99 Mendel, Johann Gregor, 9, 10, 23 Brno, Moravia, 9 Mendel's laws, 28 meningitis, 21 mentally ill, 42 Merck, 141 Mercury, 65, 68, 76 messenger ribonucleic acid (mRNA), 13, 16 metabolism, 155 metastasized, 93 meteorology, 68, 125 methane gas, 154, 162 Methanococcus jannaschii (M. jannaschii), 163 164 methanogen, 154, 163 Meyerhof, Otto, 12 Michio Kaku, 14 microarrays, 25 microbes, 149, 152, 154, 157 158, 161 162, 164 166 microbes' oil, 162 microbial biology, 158 159, 162 163 microbial cells, 160 microbial diversity, 157, 161 microbial genome project, 162 microbial genomes, 162

microbial sequencing, 163 Microbiological Reviews, 161 microbiology, 126, 149, 151, 156 157 cultured, 158 microorganisms, 149, 162 cultured, 158 microscope, 149 microscopic organisms, 148 Microsoft Windows, 25 Microwave Anisotropy Probe (MAP), 113 Milky Way, 63, 70, 77, 110 Mill, John Stuart, 134 social utility, 134 Mindwaves, 39 Mingus, Charles, 84 Minsky, Marvin, 41 Miranda, 58 Mirkwood, Galadriel, 87 The Journal of Experimental Immunology, 87 mitochondria, 154 molecular binding sites, 46 molecular biochemistry, 46 molecular biological revolution, 89 molecular biology, 13, 20, 51, 80, 86, 150 molecular evolution, 152, 160 molecular genomics, 23 molecular immunologists, 98 molecular immunology, 80, 89 molecular sequences, 153 molecules, 161, 165 as "chronometers," 161 Monastery, 55

Monterey Bay Aquarium Research Center, 160 Mooney, Harold, 125 Morell, Virginia, 153 moths, 124 motmot, 123 Mount Hamilton, 59, 70 Mount Palomar, 106 Mount Tromlo and Sliding Spring Observatory, 117 Mount Wilson, 55, 57, 59 60, 69, 76, 106, 170 Mr. B's, 84 Mthanococcus jannaschii, 23 mu meson, 114 Muller, Richard, 105, 106, 108, 109, 120 Mullis, Kary, 14 Murray, R. G. E., 155 Muslims, 21 mutate, 165 Myers, Norman, 139 myosin, 17 Myriad Genetics, 22 mysterians, 42 N Nabhan, Gary, 138 Naipaul, V. S., 173

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NASA, 66, 69, 72, 74, 76, 113, 148, 154 155 AMES Research Lab, 109 Hands-On Universe program, 112 Innovative Research Projects Grant, 64 Microwave Anisotropy Probe (MAP), 113 National Science Foundation, 110, 112, 116 National Academy of Arts and Sciences, 156 National Academy of Sciences, 146, 148 National Cancer Institute, 89, 98 National Geographic, 71, 125 National Human Genome Research Institute, 25 National Immunological Association, 87 National Institute of Allergy and Infectious Diseases, 97 National Institute of Health in Cellular and Molecular Immunology, 88 National Institutes of Health, 3 4, 12, 15, 17 19, 21, 26, 30, 79, 81 82, 87 89, 92, 94 96, 161, 171 172, 176 National Jewish Center, 148 National Kidney Foundation, 97 National Park Service, 162 National Science Foundation (NSF), 30, 66, 132, 176 National University of Mexico, 136 natural history, 150 natural toxins, 47 Nature, 15, 21, 38, 65 66, 70 71, 79, 85, 88, 96, 126, 140, 157, 172 Nature's Services, 139 140 Nebulae, 106 necrosis, 91 93 "Neonatal Tolerance Revisited: Turning on Newborn T Cells with Dendritic Cells," 94 Nelson, Karen, 164 Neurochemistry International, 48 Neuron assemblies, 52

neurones, 33, 37 neuroscience, 2, 4, 31, 32, 52 neuroscience conferences, 33 neuroscientist, 31, 33 neuroscience revolutions, 141 New Guinea tribes, 19 New York Review of Books, The, 48 New York Times, The, 10, 19, 27, 48, 71, 75, 77, 94, 97, 116, 118, 125, 140, 155, 165 New York University, 37, 48 Newport to Bermuda Yacht race, 27 Newsweek, 124, 140, 143 Newton, Isaac, 42, 151 Nightline, 65 niobium, 105 nitrogen, 163 nitrogen cycle, 145 Nobel Prize, 10, 12, 13, 19, 20, 27, 33, 40, 80, 88, 103 Northwestern University, 100, 152 nuclei, 154, 165 nucleic acids, 151, 153 nucleus, 154 O oligonucleotide, 153 Olsen, Gary 157 159, 163, 166 Olsen, Maynard, 22, 24 ontology, 95 opportunistic science, 2 Oregon State University, 137 organelles, 154 organic chemistry, 35 organic material, 165 organic molecules, 165

organisms, 148 149, 151, 159, 161 162, 166 oscilloscopes, 60, 172 Overbeek, Ross, 161, 163 Overbye, Dennis, 106 Oxford Instruments, 45 Oxford University, 31, 34 36, 38 39, 41, 45 47, 50, 52, 91, 169, 171 P Pace, Norman, 147 149, 156 160, 163, 165 166, 170, 173 Packard Foundations, 138 pancreatic cancer, 99 Pardoll, Drew, 83 Parkinson's disease, 37, 39, 45 46 Parliament, 49

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particle accelerator collisions, 63 particle accelerators, 104, 109 particle physics, 103, 113, 119 patents, 18, 19, 22 pathogens, 21 Paton, William, 32 Paul, William, 92 Pauling, Linus, 10, 30, 153 Pegasus, 65, 77 penicillin, 40 Pennypacker, Carl, 105, 106, 108, 109, 110, 112, 118, 121, 170, 172 Pennypacker F/1, 109 Penrose, Roger, 39, 42, 48 peptide, 46 Perkin, Elmer, 26 Perlmutter, Saul, 4, 33, 104 106, 108 122, 169 177 petroleum, 162 Pew, 139 Pew Fellows, 137, 143 Pew Fellowship, 133 Pew Foundation Fellowship in Conservation and the Environment, 137 Pfizer, 46 pharmacology, 41, 46 Phobos, 58 photographic emulsion, 109 photosynthetic, 158, 164 physiochemistry, 42 Pinker, Steven, 42 plant hybrids, 9 Plato, 32, 42, 177

pneumonia, 87 policy studies, 135 Pollard, Ernest, 150 pollinators, 124, 139 140 Popper, Karl, 82, 90, 92, 99 100 Population Bomb, The, 127, 136 Postel, Sandra, 129, 131, 138 President's Council of Advisors on Science and Technology, 143 primitive bacteria, 164 primordial, 149 Princeton University, 116, 119 Proceedings of the National Academy of Sciences, The, 155, 165 programmed cell death, 91 prokaryotes, 150, 154 prostheses, 80 prostitution, 144 proteins, 150 151, 154 psyches, 3 psychotropic drugs, 42 pulsation, 70 71 Purity Springs, 139 Pym, Barbara, 34 Q Quonset hut, 7, 59, 62 quantum physics, 3, 10 quasars, 109 Queloz, Didier, 65, 76 R radial velocities, 63 Rasio, Fred, 71 Recording Company of America (RCA), 173 red dwarf star, 75

Gliese 876, 75 redshift, 107, 111, 112 rejection of transplants, 94 relativity, 150 remote sensors, 2, 3, 125, 175 renal cancer, 99 Rensburger, Boyce, 80 restriction enzymes, 20 "reticulate evolution," 165 rhesus monkeys, 97 ribonucleic acid (RNA), 16, 30, 148, 153 154, 157 158 ribosomal nucleic acids, 155 ribosomal RNAs (RNA), 153 156, 158 159 ribosome, 153, 165 Ridge, John Paul, 94; see also "Neonatal Tolerance Revisited: Turning on Newborn T Cells with Dendritic Cells" Riess, Adam, 117, 118, 120, 121, 122 Ritalin, 42 River Chewell, 34 Robb, Frank, 163 robotic telescopes, 108 Roche, 22 Rochester University, 95 Rocky Mountain Biological Laboratory, 128

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Roosevelt, Franklin, 89, 141 Rosalind Franklin and DNA, 29 Royal Air Force, 47 Royal College of Art, 31 Royal Greenwich Observatory, 109, 110 Royal Institute, 4, 50 52, 169 "Christmas Lectures," 43, 52 Director of, 49, 52 Royal Society Proceedings, 131 Royal Swedish Society, 134 Rutherford, Earnest, 151 S Sacks, Oliver, 42 Sagan, Carl, 43, 75 Sagoff, Mark, 145 Salk Institute, 86 San Francisco State University, 60 61, 64, 69, 77, 171 172 San Vito, 123, 125, 135, 142 143 Sanchez-Azofeifa, Arturo, 142 Sandage, Allan, 55, 77, 106, 121, 170 Sanger, Fred, 13, 16, 153 Sanger Center, 26 Santa Fe Institute, New Mexico, 133 sarin, 36 satellite imaging, 125, 142 Saturn, 59, 77, 175 Saturn Titan, 58 Sayre, Ann, 29 "schlepper, the," 93 Schmidt, Brian, 113

Schneider, Stephen, 129 Schrödinger, Erwin, 10 What Is Life?, 10 Schwab, Robert, 85 Schwartz, Ron, 82, 87 89, 92, 95 96, 99 100, 172, 176 Science, 21, 22, 79, 85, 94 96, 99, 116 117, 119, 121, 140 141, 149, 153, 172 Scientific American, 85 Scientist, The, 166 search for extraterrestrial intelligence (SETI), 66, 173 Searle, John, 39, 48 Second World War, 20 self/nonself theory, 80 81, 83, 85 86, 90 92, 98 99 sequence, 151, 159 sequencing, 159 Sexton, Anne, 79 Shoemaker, Carolyn, 173 Shoemaker, Gene, 173 Shoemaker Levy 9, 173 short sequences, 148 shotgun genomics shotgun DNA cloning, 16, 17, 18, shotgun gene sequencing, 174 175 Shreeve, Jim, 22 sickle-cell anemia, 28 signaling, 98 Silicon Valley, 109 silicon wafer, 109 Silver, Anne, 37 Silverstein, Arthur, 94 95, 97 Simon, Julian, 136 simple cells proliferated, 165 single-celled, 156

Sloan Digital Sky Survey, 113 Smith, David, 23, 31 32, 35 41, 47 Smith, Douglas, 164 Smith, Hamilton, 20, 21, 29, 163 Smith Kline Beecham, 23, 27 Smithsonian Institution, 172 snake toxins, 47 sociology, 135 software, 125 Sogin, Mitchell, 152 153, 167 Southern Hemisphere, 69 Space Interferometry Mission (SIM), 76 Special Tropical Lecture, 95 species, 152, 158 spectra, 107 spectrograph, 63, 172 spectrometers, 70 spectrum, 62 Spergal, David, 116 Spiegelman, Sol, 151 Spring, Leslie, 97 Springy, 34, 46 Squibb, 41 Srivastava, Pramod, 96, 97 99 St. George's Hospital in London, 97 St. Hilda's College, 34 35 Stahl, David, 152, 159, 161 Stanford University, 22, 127, 131, 135, 146, 152, 171

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Stanier, Roger, 152, 155 star atmospheres, 56 star systems, 3 Star Wars, 45 Stein, John, 36 38 Steinberg, Wallace, 19, 20, 23, 24; see also Human Genome Sciences Steinhardt, Paul, 119 "Stellar Radial Velocities," 62 Live, 79 Stetter, Karl, 160 stillborn, 67 Stork and the Plow: The Equity Solution to the Human Dilemma, The, 135 136, 144 stromatolites, 160 Structure of Scientific Revolutions, 156 structures, 154 subgiants, 74 Substantia nigra, 45 sulfur, 159, 162, 165 sulfur nitrate, 33 sulfuric acid, 154 sulfuric caves, 149 Sun Microsystems, 69, 71, 173 sunspots, 9 Superconducting Supercollider, 105 Supernova, 4, 106 116, 119, 121, 122, 169, 173, 175 Supernova Accelerator Probe (SNAP), 122 Supernova Cosmology Project, 110, 112, 120, 121 Sutton, Granger, 20, 29 Sutton, Lee, 152 swapping, 165

symbiosis, 159 symbiotic communities, 158 Synaptica, 46 47, 49, 51 52, 172, 176 synthetic antibodies, 97 syphilis, 21 Szent Györgyi, Albert, 41 T Tacrine, 46 tanagers, 123 Taq enzyme, 162 Tarter, Jill, 66 T-cell, 86, 88 T-cell memory, 81, 91 T-cell receptors, 89 Terrestrial Planet Finder (TPF), 76 The Institute for Genomic Research (TIGR), 20, 21 25, 163 164, 176 scientific advisory board, 163 TIGR Assembler, 20, 29 theoretical model, 138 theory of evolution, 3, 91, 100 thermomicrophilic microorganisms, 160 thermophiles, 158 159 Thermophilic Microorganisms and Life at High Temperatures, 158 Thermus aquarius (Taq), 162 third domain, 148 Thomas, David, 46 thymus, 88 TIGR; see The Institute for Genomic Research time travel, 9 Times, The, 8, 43 44 Tirumalai, Kamala, 100 tissue engineering, 81

Titan, 59 Titanic, 55 T-lymphocyte, 86 tolerance, 81 "Tolerance, Danger, and the Extended Family," 93 tones, 63 "total" values, 140 transfer RNA (tRNA), 151 "translation," 150 transplanted organs, 94 TREE, 141 Trixie, 83 tuberculosis, 144 tubeworms, 158 Tufts University, 41 "Turned On by Danger," 95 Turner, Michael, 117, 120 Twilight Zone, 58 Type 1 Diabetes, 80, 97 U United Nations, 38 United States Department of Energy (DOE), 162 163 Universal Ancestor, 156, 165

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University of Alberta, 142 University of Arizona, 44 University of British Columbia, 62 University of California at Berkeley, 60 61, 66, 77, 105, 109, 111, 112, 114, 129, 152, 172 University of California at Irvine, 84 University of California at Los Angeles (UCLA), 45, 57, 59 University of California at San Diego, 11, 14, 85, 164 University of California at Santa Cruz, 59, 75 University of California, 23, 39, 61, 108, 111 University of Chicago, 117 University of Colorado, 157 University of Connecticut, 96 University of Georgia, 153 University of Illinois, 23, 148, 151, 152, 157 158, 163 University of Iowa, 69 University of London, 46, 72 University of Maryland, 163 University of Miami, 97 University of Michigan, 14 University of North Carolina, 152 University of Pittsburgh School of Medicine, 97 University of Regensburg Laboratory, 160 University of Southern California, 160 University of Sussex, England, 72 73 University of Washington, 25 University of Wisconsin, 158, 162 uracil, 153 Uranus, 58 U.S. Naval Hospital, 97 U.S. Naval Medical Research Center, 97

U.S. News and World Report, 140 V Van Niel, C.B., 152, 155 vaccines, 94 Varmus, Harold, 3, 89 Vaughn Johnny, 75 "The Big Breakfast," 75 Vaux, David, 45 47 VAX minicomputer, 60 Velikovsky, Immanuel, 75 Velvet Underground, 31 Vent, 162 Venter, J. Craig, 4, 33, 48, 50, 63, 83, 95, 146, 163 164, 170 178 adrenalin receptors, 12, 14 brain cells, 12, 14 Haemophilus influenzae, 20, 21 Japan, 16 molecular biology, 13 National Institutes of Health (NIH), 12, 17, 19 Renaissance weekend, 9, 23 Roswell Park, Maryland, 12 Sorcerer, 9, 27 State University of New York at Buffalo, 12 Vietnam, 1, 7 10 Venus, 57 Virgo, 66 Vitousek, Peter, 137, 139 Vogt, Steve, 57, 59, 63 64, 69, 72, 77, 172 W Waldmann, Herman, 88 Waldsterben, 127 Walker, Gordon, 62

Wall Street Journal, The, 19, 94, 99 Warrick Couch, 109 Washington Post, The, 75, 116, 140 Watson, James, 10, 15, 18, 19, 24 27, 30, 87, 141, 150 151, 170, 174 Double Helix, The, 11 wave interference sensors: see interferometers Weinberg, Steven, 107 Westinghouse, 23 Westinghouse, George, 23 White Stallion Ranch, Arizona, 137 Whitman, William, 153 Williams College, 64 Wilmut, Ian, 130 Wilson, E. O., 29, 124, 177 Consilience: The Unity of Knowledge, 177 Wilson, Robert, 60 Winslow Heinz, Postdoctoral Fellowship, 133

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Woese, Carl, 4, 23, 92 148 157, 159 161, 163, 165 167, 170 172, 174 177 Woesean tree, 157, 161, 164, 166 Wolf, Nancy, 45 Wolfe, Ralph, 151, 154 155, 163 Wood, Martin, 45 46 woodpecker, 128 Woods Hole Program, 152 World Economic Forum, 144 World Series, 74 World Wide Web, 44 45 Worlds in Collision, 75 Worldwatch Institute, 129 Wright, Robert, 174 Moral Animal, The, 174 Wright Institute, 42 X x-ray crystallography, 10; see also Franklin, Rosalind Y Yale University, 150, 157 yellow-green atmosphere, 165 Yellowstone, 149, 162 Young, Dick, 154 Z Zimmer, Carl, 160 Zuckerkandl, Emile, 153

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