I,Stuart Schreiber says, sotto voce, “am ecstatic in my life.”

It is the least academic of settings. The office is large, irregularly shaped, orderly, serene, and sleek as a $300-an-hour Miami lawyer’s. Bold expressionist paintings, suffused by recessed lighting and the warm halo of a black torchère, broadcast a taste for art and for expensive design trends. In that part of the room where an earlier generation of chemists would have anchored an ancient seminar table seared with cigarette burns and coffee stains, gleams an immaculate, low-slung glass and steel cocktail table encircled by a perfectly equilibrated constellation of plush chairs. Anchoring here is an imported olive green sofa, leather soft as vellum.

Schreiber himself is tall and supple, not wide, but no longer lanky either. In his mid-thirties, he still brims with a kind of boy-wonder enthusiasm, as if stunned by his own cleverness. His speech is smooth and precise, though sometimes, when he thinks he has gone too far or revealed too much, it trails off in an Annie Hallish vacuum of awkward self-censorship. With a cleft chin swathed in a semipermanent three-day beard (“so that when you sit on airplanes, little kids and old ladies don’t want to talk to you,” he says), chestnut cheeks, goggle eyes, and a receding cap of stylishly cropped prematurely gray hair, he coils in a sidechair with the poise and equanimity of an ostrich, just as Boger, at his desk, resembles a crane.

His aestheticism, his sense of perfection, extends beyond himself and his office to his labs. Most university laboratories are grim, utilitarian places, scruffy and metallic, like the waiting rooms of welfare offices. Schreiber’s gleam strenuously. The hoods are a brilliant tomato red, the cabinets blond. In the cold room, a floor-to-ceiling picture window ensures that his students won’t have to suffer unpleasant isolation while conducting their experiments. When Schreiber arrived from Yale in 1988, Harvard assigned him two wings in contiguous buildings joined only by a hallway. At his insistence, it built a lounge to connect them—a move that required filling in all the floors above and below. “I’m sure this is the most expensive lounge Harvard ever built,” Schreiber says, “but it’s worth it.”

That nurturing Schreiber’s “personal equilibrium” is “worth it” few Harvard administrators would dispute. Like all research institutions, Harvard is a business. Its products are ideas and scholars, and its relationship to its senior professors, particularly in the sciences, largely that of a central bank. From that standpoint, Schreiber’s fusing of synthetic chemistry, which he is trained in, with cell biology, which he’s not, promises to be a bonanza, and Harvard has supported him avidly. Having saved itself—and lost a fortune—with the first round of biotech companies spawned by its professors, Harvard has been eager not to neglect the “major industry” in small molecules that Schreiber believes he is now inventing in its labs.

“The day I realized I was going to move” from Yale, he recalls, “I compiled a list. I thought it was fairly responsible, but I was worried that they would be upset by it. I know the Yale administration would have gulped. Suffice to say I put my figure down and they immediately came back with a counterproposal that was larger than that figure.

“That’s when I realized I’m not dealing with a nickle-and-dime group. These are people who are deadly serious about the sciences.”

So much euphoria, such great good fortune, might be expected in so young a researcher to unleash a ranch-sized ego, and Schreiber is far from modest about his status in the new Harvard plutocracy. “This is where I had to be,” he muses. “I knew I would end up at Harvard. I knew it! Whatever it would take I would achieve that. I wouldn’t stop working until I got there. If I had to give up everything else, I would be willing to do that.” On the other hand, his self-awe seems largely to devolve from and be measured against Harvard’s singular history. “This is the Mecca for organic chemistry. It always has been. I quickly came to the conclusion that, yes, I was good at certain problems in synthetic chemistry. I had published manuscripts that basically caused people to say, ‘Gee, he’s a clever fellow.’ But being here, you realize that’s not good enough. You’ve got to create something new.”

This was Schreiber’s charge to himself in late 1988 and early 1989 as he assembled his labs: to do something new in chemistry, something creative, beyond mere cleverness. Indeed, it was greater than that. Equating his call to Harvard at age thirty-two with a thirty- to thirty-five-year mandate to advance the frontiers of organic chemistry, he set out to redirect and enlarge the field. Like previous generations of synthetic chemists, he would concentrate on making biologically active molecules. But he wouldn’t stop there. He would use those molecules as probes, to uncover a wider world. Exploring how small molecules affect intracellular processes, he would push chemistry to the very heart of the revolution in biology.

It was a potentially historic manifesto. For decades, cell biology had been moving to a more molecular understanding. At the same time, its principal tools and methods came from biology, particularly the recombining of genetic material. And yet biotechnology had its limits. A wide array of protein receptors on the surfaces of cells had been identified, for instance, using genetically engineered probes, spawning a new generation of drugs and drug research. But such molecules were too big to penetrate the cell membrane.

Here was Schreiber’s vector, his opportunity: small molecules. He resolved to use smaller, synthetic compounds to breach the cellular barrier. He would make molecules that could be used to identify proteins in the cytoplasm, extract them, purify them, elucidate their architecture, identify their partners. He, a chemist, would penetrate and explain the most fundamental biological events—the chemical interfingering of molecules inside cells. He even had a model: FK-506. Schreiber determined to use the molecule and variants of it, like 506BD, to attack the most hermetically encoded secrets of the cell: how proteins, which are made of lifeless atoms, talk to each other, how they travel purposefully within the nexus of the cell. He would answer questions that biologists usually ask, and he would do it better, faster, more brilliantly, by using new molecules that only he—and those Harvard licensed them to—had.

“Biochemists,” runs an old definition, “are people who talk about chemistry to biologists, about biology to chemists, and about women among themselves.” For more than a generation, the leading biochemists had mostly been molecular biologists, people who looked at life through the prism of DNA. To understand biology at its most basic level, they said, one must start with the gene—the act of creation. Schreiber took a more situational view. He would start with the trigger of all biochemical events: the binding of two molecules. Changing how molecules bind, he would revise their structures, affect their activity, and demonstrate the physical relationship between the two. He would use his knowledge of chemistry to explain biology and perhaps, in so doing, alter it.

This was Schreiber’s mission, his trajectory.

Of course, he wasn’t alone. That Boger, another Harvard-trained nonbiologist whom Schreiber then knew only slightly and who indeed thought of him as just such a “clever fellow,” should just then have embarked on the same path with the same molecule was surely the most startling and epic coincidence in either of their lives.

•  •  •

Once at Harvard, Schreiber moved quickly to consolidate his charter. He’s prone to epiphanies, and when he’s had one, it prompts in him a dauntless confidence. He places himself, as Mark Murcko puts it, “above the noise.” Schreiber had catapulted himself to a central place in immunophilins research by collaborating with Harding on the discovery of FKBP. He had furthered his priority by having his group isolate the gene that encoded the information for making the protein, then, borrowing recombinant technology, cloning it and churning out new protein by the Thomson Unit. At each stage, his luck had been enormous. He had never discovered a protein before, never cloned a gene, never overexpressed an enzyme. Yet he and his network of students and collaborators had routinely tied or won against some of the best labs in the world. Calling FKBP a “blessed molecule,” which for Schreiber and his students it surely was, he now sought to use it to make his mark on all science.

That Schreiber should be doing all this at Harvard was easily as surprising as the successes themselves. Certainly nothing could have been further from his own view of his future when, as a profoundly indifferent high school student, he enrolled in a work study program so he could avoid taking classes, then skipped those few that were required. “I was not academically oriented whatsoever,” he recalls. “I never thought about going to college. I thought about being a carpenter. I was thinking about whether I wanted to do flooring or roofing. That was the level of resolution I was considering. I really didn’t think I needed college; those people were so uninteresting to me.”

What interested Schreiber, growing up in semisuburban Virginia in the 1960s and early 1970s, were dirt bikes, sports, carousing, and girls. His father, a retired army colonel and ballistics consultant, was a strict disciplinarian; his mother, a doting homemaker, uncritical of her youngest son. Yet both his parents resolved to let their children live their own lives. Working at a pizza shop, Schreiber became a virtual stranger at school. “I never had a book in high school,” he recalls. “They gave me books at the beginning of the year—I never thought this was odd—and a locker and a combination. I took the books, put them in the locker, then at the end of the year, they asked for the books back, so I had to go back and ask for the combination. I never once went to the locker during the year.” Schreiber was a shop rat. He took Shop 1, 2, and 3, electronics, automotive maintenance and repair, and a course he remembers as “bachelor wardrobe planning”—the boys’ equivalent to home economics. It was taught, he recalls, by “a thick redneck guy who told us about his escapades, which involved either beating up people or chasing women.”

“I never heard of chemistry until my last year,” he says. “They brought us into the auditorium and we watched a Walt Disney movie. That was our introduction to chemistry. My impression was that chemistry had some analogy to the planets rotating around the sun.”

Despite his lack of motivation, Schreiber seemed to have an uncanny ability to absorb certain information, particularly at test time. He had a flair for abstract concepts and a kinship with shapes. “I thought there was something strange about me. I was able to sit down and figure out a geometry exam right on the spot. And yet I hadn’t been to the classes. Everyone else was complaining about how difficult it was, but it just seemed so logical to me.” A guidance counselor suggested he take the SATs. Racing through the six-hour exam after a night of “raising hell,” Schreiber scored among the highest in his class. “I remember people saying, ‘Sheeee. Schreiber! How the hell did he do so well?’ ”

On a lark, he decided to apply to the University of Virginia (U.Va.) and Virginia Tech. “I didn’t really care if I got in or not—in the back of my head I was still thinking about roofing or flooring. But I did get in, which was another big surprise.”

In most hagiographies there comes a period of bitter wandering before the advent of a profound vision. Such is how Schreiber describes his arrival at U.Va. He was miserable. He didn’t want to be there. The students were nothing like his buddies back home at the pizza shop. Thinking he might want a career where he could work outside, he contemplated biology and forestry, but was told he first had to take chemistry, a notorious “flunk-out course.” Schreiber considered the fact that he’d never studied before, thought about Walt Disney and his revolving orbs, and signed up for all liberal arts courses instead. “I absolutely hated it,” he recalls. “In one course we had to read Sartre’s No Exit. There were a lot of Northerners, and they took the book so seriously. It made me want to vomit.

“I quit going to classes. I spent my first three weeks absolutely convinced that I was leaving the university, which was fine with me. Then I realized that I could take advantage of my street sense and have a lot of fun. I realized there were a lot of young women I could spend my time with. So that’s what I did.

“After the third week I called my sister and told her I was going to quit. I explained why, and she said, ‘Well, you should do what you want to do. You should take the chemistry course if that’s what you want.’ The minute she said it, it seemed perfectly reasonable: Well, of course, take the chemistry course. I went and saw the instructor. He told me, “You missed the first three weeks. The first exam is on Friday’—I think this was Monday. He said, ‘I’ll let you into the course, but you will not be excused from taking the first exam.’ ” Schreiber laughs. “I thought, ‘What difference does that make to me?’ I didn’t care about failing an exam. I obviously wasn’t going to make it, so fine, great with me.”

He continues: “Now that Monday, that was a very important day. I went into the big lecture hall. That was the first time I’d been in a real bona fide lecture. I remember my first impression. I walked into this room, I looked around, and everybody had notebooks, and they were taking notes. And I wondered, ‘How did everybody know to do this?’ So I asked someone. I said, ‘How did you know to get a notebook? Did somebody tell you? Did I not get something?’

“I sat in on that lecture. The instructor—his name was Russell Grimes—went to the board. And he started drawing something that I had no idea about. It turned out he was drawing atomic orbitals. In fact, he was discussing a set of five d-orbitals. These are sort of geometric shapes. They have large lobes. One of them has two large lobes and a donut ring around the intersection of the two lobes . . . He used colored chalk.

“I looked at that and thought, ‘My God! This is chemistry? I thought chemistry was like the planets revolving around the sun. This seemed like geometry. It was spectacularly beautiful, with great aesthetic appeal in what he was drawing. I had no idea what it was. But the colored chalk. The different shaped orbitals. I thought, ‘This looks really interesting.’

“I went down to the bookstore and bought the book. I took it back to my room. I decided, ‘OK, here’s where I run into my dead end.’ I had heard, around the dorm, a lot of the students complaining about how difficult this was and how they didn’t understand it. So I read the first chapter, carefully, sentence by sentence, waiting to be told something that was uninterpretable and it just never happened. It all flowed so wonderfully. It seemed so clear and logical.”

Cramming, Schreiber got an eighty-eight on the exam, missing just three questions—“the last three problems I missed for the rest of the year,” he recalls. “After that, I started going to every lecture. I couldn’t get enough of this. It was really exciting. It was absolutely clear to me that I was really good at this, and I really loved it.”

Schreiber was now on the road to Damascus. He discovered that the next course was organic chemistry, which he found “orders of magnitude more interesting” than general chemistry. Insatiable, he bought the second-year text and pored over it throughout the summer. “I pretty much mapped out my career at that stage,” he says. “I remember going to the chairman of the department. I’d read through the graduate brochure and knew what everyone was doing. I sat down and said, ‘I’ve given a lot of thought to what I’ve studied and I want do synthetic organic chemistry in my career. I want to be a synthetic organic chemist. I want to be a professor at a major university, probably on the East Coast. And furthermore, I want to work in your laboratory.’ ”

He still hadn’t entered his first lab or run his first reaction, but Schreiber, at age nineteen, now devoted himself to a life of making complex molecules. “I went from two incredible extremes—no academic orientation to this tremendous passion for organic chemistry. Then I learned synthetic chemistry, and that was truly exciting. I realized that it was much like studying architecture. You have this complex target molecule and a large collection of reaction processes. Then you have to analyze logically a sequence of reactions that will take simple materials and convert them to complicated materials, just like building a new building. There are an infinite number of solutions, but some are clearly characterized by elegance and efficiency. There is an aesthetic appeal to the way you assemble a certain number of these smaller fragments and they just snap together. You know you’ve got it. There are other ways of doing it, but they’re not as interesting.”

Schreiber fancied himself a master synthetic chemist from his first moment at the bench, although now he concedes that the pace of his research was “pitifully slow.” It hardly mattered. He was a phenom, a natural. By the end of his sophomore year, he was devouring chemistry texts in rapid succession and compiling an academic profile so hyperattenuated to one discipline that the university didn’t know what kind of degree to grant him. Of 120 total undergraduate credits, he amassed 105 in the sciences, 85 of them in chemistry. He took every graduate course in the department and got straight A-pluses. Totally dedicated, he abandoned all other pursuits, considering them hopelessly dull. By the time he graduated, he recalls, “I had tremendous confidence in myself. I don’t think I was an arrogant person. I wasn’t hard to get along with. But I knew I was very good at this.”

Schreiber had entered college not knowing how students knew to take notes and left it gaining automatic acceptance to Harvard, the best organic chemistry department in the world. What’s more, he had come, by the supple ease with which he managed everything associated with his new path, to expect no less. “Harvard acceptance? Of course! They had to take me!” he says. He had begun an uneducated naif and ended a wunderkind, bionic. There was little question what was next for him. Arriving in Cambridge in the fall of 1977, Schreiber quickly approached Robert Burns Woodward, by almost every estimate the greatest synthetic organic chemist of the twentieth century, and asked to study in his lab. A towering, romantic figure already well on his way to beatification, Woodward indifferently agreed.

Four years after his introduction to science—to books—Stuart Schreiber had entered the holy city. Immoderately, typically, he chose to set himself against perhaps its greatest living icon.

•  •  •

Claiming six U.S. presidents, thirty-three Nobel laureates, and twenty-five Pulitzer Prize-winners, Harvard competes only with itself in the manufacture of academic legends: Institutional narcissism is the weather in which Harvard egos move and grow. Yet few Cambridge personalities have ever been as encompassing, as jealously revered, as R. B. “Bob” Woodward. “What was Woodward like?” shrugs a colleague of more than forty years. “He was a genius.” Says Schreiber: “He absolutely, completely overshadowed everyone else in the field. If Woodward walked into the lab and said, ‘Cut off your arm,’ you’d ask, ‘Which one?’ ”

Woodward knew he was great: He’d always known. Arriving at MIT in 1933 at age sixteen, he already had taught himself more chemistry than the university expected of departmental majors. By his sophomore year, the faculty voted to give him his own laboratory and stipend and excuse him from attending classes. He responded by taking fifteen courses in a single semester and finishing his Ph.D. at age twenty. From there he went to Harvard, entering as a postdoc in the fall of 1937 and taking over Tishler’s former lab on the third floor of Converse Hall. (The scene of Tishler’s dramatic fire and rescue, it is now part of Schreiber’s biology wing.)

“None of us thought he was really that great,” Tishler would recall. “He had such great press. He was also sort of irritating.” But Tishler and Woodward soon became close mutual admirers, united by an obsessive devotion to making molecules. Tishler wanted to prove that any compound that could be made could be made commercially; Woodward, that any molecule found in nature, no matter how complex, could be synthesized in the lab. They were kindred spirits whose informal synergy came to dominate synthetic organic chemistry for the next forty years.

“Max,” observes Peter Jacobi, chairman of the chemistry department at Wesleyan, who worked with them both, “thought Woodward was the best chemist who ever lived.” Surely he was among the most Promethean. In 1943, at the height of World War II and at age twenty-six, he synthesized quinine, helping to break Japan’s stranglehold over natural supplies of the drug. Four years later, he again stunned the world by stringing amino acids together into proteinlike chains—“silk that doesn’t come from worms, wool that doesn’t come from sheep, and fur that doesn’t come from any fur-bearing animal.” Though he claimed not to emulate God—asked once if he hoped to synthesize life, he said, “No, I am quite happy with the way it is done now”—he deemed to match himself against nature at a higher level than any chemist before him.

In 1949, under a contract from Merck arranged by Tishler, Woodward undertook the total synthesis of cortisone. For five years, the company had struggled to produce the drug from ox bile with prohibitive results; it took the slaughter of forty head of cattle to treat one patient for one day by a process with forty-two chemical steps. Tishler ultimately would condense the synthesis to a more manageable—and profitable—twenty-six steps in what an admiring Woodward called the greatest feat in the history of commercial chemistry. But Tishler believed—and Woodward agreed—that if cortisone was to become universally available, it had to be made from a starting material more abundant and less gruesome to obtain than the precious fluids of bovines. As the New York Times reported, the competition to produce the drug from another source had become “the greatest international race in modern chemistry in which the world’s top chemists have participated.”

Woodward, still in his early thirties and released the previous year by Harvard from teaching so he could work on the effort fulltime, was relentless. Chemists had learned to make steroids, large multiring compounds, from other steroids, but no one had yet made one from scratch, the way nature does, by assembling them from individual atoms. Using a derivative of coal tar, Woodward learned how to direct groups of atoms to reshuffle, like dancers at a reel, into the precise shapes he was seeking. The result wasn’t cortisone, but another steroid equal to Merck’s ox bile derivative for staging cortisone’s final synthesis. At twenty chemical steps and made from cheap, clean, abundant materials, Woodward’s steroid represented a breakthrough of stunning scientific and commercial appeal, auguring the availability not only of cortisone but of the entire family of human hormones.

The announcement of Woodward’s discovery in April 1951, at the height of Merck’s crisis in supplying the drug to a cortisone-starved world, was incandescent. “The achievement was hailed . . . as ‘one of the greatest in the history of chemistry’ . . . of ‘incalculable importance’ to millions of sufferers from rheumatoid arthritis, rheumatic fever, burns, blindness-causing eye diseases, and a host of other chronic ills, as well as for the future welfare of humanity,” the Times reported on page one. Woodward himself was less breathless. “We have not yet synthesized cortisone,” he said. “I don’t know how many operations will be required before we get cortisone nor how long it will take. It may even be impossible.”

In fact, Woodward was right; the discovery was less epochal than it appeared. Synthetic chemists were enthralled, but they no longer defined what was important in the life sciences. The far bigger story that spring belonged to Linus Pauling, a biochemist at the California Institute of Technology who had, after fifteen years of work, published a series of papers that would affect the future of organic chemistry substantially more than Woodward’s synthesis. Pauling, a puckish, brilliant experimentalist who would go on to become one of only three people ever to win two Nobel Prizes, one in chemistry and one for his disarmament work, had determined the essential rules by which proteins folded.

Pauling’s discovery, like Watson and Crick’s a year later of the structure of DNA, inverted the hierarchy of science. For seventy-five years, reseachers had been baffled about whether proteins conformed to discrete shapes and whether those shapes determined their activity. Pauling not only answered with a resounding yes, but detailed all the major motifs by which they were formed. Instantly, as chronicler Horace Freeland Judson has observed, the structure of molecules—not their chemical composition—became “the central and most productive question of modern chemistry.” In structure lay function, and what a molecule did determined its importance. Synthetic chemistry, which didn’t explain molecular behavior but only reproduced it, fell in stature.

More disappointments were to follow. Tishler had hoped that the Merck-Woodward collaboration on cortisone would cement a long-term alliance, but though Tishler and Woodward valued their connection, others were less comfortable. Woodward eventually arranged to consult with Pfizer, one of Merck’s chief competitors. “This broke my heart,” Tishler would say almost forty years later. “We had a problem. There were one or two people who wouldn’t tolerate bringing him in because they thought he’d take over.” Worse, in July, less than three months after Woodward’s announcement, Syntex, a little-known drug company with laboratories in Mexico City, disclosed that it had succeeded in making cortisone from a wild, inedible Mexican yam. The process was cheaper than Woodward’s and Tishler’s combined syntheses, and Syntex quickly went on to become the world’s largest maker of cortisone and other hormones despite Merck’s earlier lead. Salting the wound, the average age of Syntex’s chemists on the project was twenty-seven. Woodward, like many prodigies, had exulted in his youth, saying that most synthetic chemists were through by age thirty-five. Now he was thirty-four—two years older than Schreiber would be when Schreiber was recruited to Harvard—and had so increased expectations about what molecules could be made that other chemists were beginning to surpass him.

Woodward continued to make more and more complex molecules—chorophyll, lysergic acid, strychnine. (“If we don’t make strychnine,” he vowed characteristically, “we’ll take strychnine!”) In 1965, he won the Nobel Prize in chemistry, then in 1972 went on to synthesize vitamin B₁₂, the most complicated synthesis up until that time and a feat so extraordinary that many chemists believed that he, like Pauling, would eventually win a second Nobel Prize for it. That he didn’t only seemed to drive him harder to expunge the stigma of having won just one.

Woodward labored toweringly. He seldom slept more than a few hours a night. He reviled wholesomeness, which he blamed for most of the problems of others, and smoked and drank with ferocious abandon. “We generated three axioms about Woodward,” a former postdoc would write. “He never got drunk, he never got tired, and he never perspired.” To his students, he was a demigod, and they treated him so by bearing him half-solemnly to the podium for lectures in a blue sedan chair emblazoned with his initials.

But Woodward in a sense performed too well. He had shown that nearly any organic molecule could be made in the lab and had pioneered the methods for making them. Yet after that, each succeeding synthesis, however bold technically, could only make a narrower point. Science, like galaxies, grows fastest at its fringes, and two areas where divergent fields overlapped and shaded into each other—biophysics and molecular biology, the fields pioneered by Pauling, Watson and Crick, and others—had begun by the early 1950s to offer far more powerful means for understanding how molecules behave and why. Woodward had staked his frontier, conquered it, and stayed there, bringing synthetic chemistry to the center of the scientific world. Yet by the late 1970s, when Schreiber arrived in his lab, the greatest advances were coming almost entirely from someplace else.

•  •  •

At first, Schreiber didn’t notice the change. His newfound belief in himself and in making molecules was so exhilarating, his exaltation of Harvard, as its Mecca, so profound, that he dismissed everything else. “I felt sorry for anyone who wasn’t doing synthetic organic chemistry because they were missing out on what was so obviously the most important science,” he says. He was particularly contemptuous of biology.

Woodward by now had withdrawn almost entirely from his students, leaving them to direct their own projects. He still held late-night poker games, but Schreiber wasn’t interested in playing and so got little insight into his mentor. What he got, he explains, was an invisible hand instilling in him the confidence to take on any problem and the princely feeling of being part of an elect. “You felt very good about yourself in the Woodward group,” he says. “You felt it was rubbing off on you. People would do anything—anything—to achieve something that would capture his attention.”

Schreiber had joined Woodward in the fall of 1977, just as Boger was finishing his doctorate across the courtyard in Jeremy Knowles’s enzymology lab. Twenty-two months later, midway through Schreiber’s Ph.D., Woodward, then sixty-two, died suddenly of a heart attack at his home. Schreiber, perhaps understandably, was less remorseful about Woodward, whom he barely knew, than about himself. He had been progressing boldly, inexorably, and now his future was clouded. In fact, Woodward’s death could hardly have been more fortunate for him. It freed Schreiber to establish his own credentials as a chemist. Invited by another professor to finish his dissertation in his group, Schreiber ended up publishing, while still a graduate student, two prestigious papers on which he was sole author. Not even Woodward had escaped the necessity of a postdoc, yet Schreiber, finishing his Ph.D. in just three and a half years, was fully credentialed. Pursued hotly by other universities, he began plotting his next move.

“There were some discussions about [my] staying here,” he says. “I was invited at any point in time I wanted to, to interview, which would mean have a small group discuss my research proposals, go out to lunch, and make a decision. But everyone’s advice was ‘It’s best for you to experience a different environment, and maybe you’ll come back.’ ” As Schreiber understood, there was a subtext to this friendly encouragement. In the 120-year history of the department, only Woodward had started as an assistant professor and gotten tenure. As in Tishler’s time, Harvard maintained a maddeningly self-important, albeit unwritten, policy of granting full professorships to a vanishingly small percentage of its junior faculty. The other members of the department may have felt they were doing Schreiber a favor, and perhaps accelerating his return, by exiling him.

Schreiber, full of himself, dismissed their concern. “I never once thought about tenure. It was absolutely inevitable that I would take care of that quickly.” Nonetheless, he says, “Their advice turned out to be right on the mark. I went to Yale and experienced something I hadn’t anticipated, that I know I couldn’t have experienced here. Here I was a graduate student [who] had done very well and I would have made a transition to assistant professor. . . . Instead, I went to Yale, and I sensed that everyone there felt about me that I was the future. I was instantly a member of the faculty.”

Like Woodward when he came to Harvard from MIT four decades earlier, Schreiber was preceded in the move by annoyingly good press and a reputation for egotism; his career was in near vertical ascent and he knew it. And like Woodward, he was looking for molecules on which he could advance science and his career simultaneously. The most significant of these turned out to be a compound called periplanone-B, a synthetic aphrodisiac for cockroaches. For billions of years, virgin female roaches have been sending males into a benighted sexual frenzy by emitting chemicals called pheromones. Recognizing the possibility of using such substances to lure the insects into traps treated with insecticide, scientists had been trying for decades to isolate enough of one of the compounds to test it. In one famous attempt, a Dutch professor raised and dissected 75,000 virgin females over a seven-year period, netting just 200 micrograms—200 millionths of a gram—of active pheromone. Clearly, only by synthesis could the material—and a potential breakthrough in the multibillion-dollar pesticide business—be tested.

Schreiber, as ever, was totally dedicated to the task. For two and a half years he and an assistant worked eighteen-hour days to build a synthetic pheromone—a large molecule with a characteristically daunting ten-membered ring. The project produced endless sneering within the neo-Gothic corridors of Yale’s Sterling Laboratory, although Schreiber’s wife, Mimi, regarded it seriously enough to insist that he wash his hands carefully so as not to bring home a trail of cockroaches. Finally, on Christmas Eve 1983, the work was completed. Schreiber’s compound was so potent that several femtograms—several quadrillionths of a gram—were enough to send a half dozen male cockroaches into an orgy of sexual self-devastation. The insects immediately stood on their back legs and started flapping their wings frantically. Fifteen seconds later, they had broken antennae, gnawed legs, and tattered wings—and apparently no further appetite for arousal. “It is easy to see that they are suffering from severe sexual fatigue,” Schreiber observed dryly.

Coming during the darkest days of World War II, Woodward’s first great synthesis—quinine—was accorded high moral and national purpose, though Woodward, characteristically, cared more about the science. Schreiber’s announcement of periplanone-B, despite its potential for protecting foodstocks in cockroach-infested regions of the Third World, was made during a far more commercial era and in a year—Orwell’s 1984—in which scientific motives were particularly suspect. Schreiber was ridiculed. Along with John DeLorean, Louis Farrakhan, Bob Guccione and Michael Jackson, he was singled out by Esquire in its annual Dubious Achievement awards for creating “a dating service for cockroaches.” “Sex and Roach at Yale” quipped the Times editorial page.

But Schreiber emerged from the episode knowing now just what he wanted and where he was going. Periplanone-B attracted male cockroaches by targeting a receptor within their nervous systems. It had tremendous biological activity, which Schreiber had witnessed as the male roaches writhed frantically, flapping their wings like stuck chickens. No longer satisfied simply to make molecules, Schreiber now determined to study their interaction with protein receptors. He had ignored biology assiduously. Now he would study the biological consequences of chemical events. Woodward’s dominance of synthetic organic chemistry had created, in the end, an untenable situation for his students: They could never hope to match his example. Schreiber, infused with ambition, resolved to fulfill the terms of his own rise by launching himself anew.

•  •  •

Crossing into deeper scientific waters, Schreiber was emulating perhaps the noblest fraternity in science: those apostates who have departed, and exceeded, their host disciplines by plumbing what French microbiologist Louis Pasteur called “the mysteries of life and death.” Ehrlich, Pauling—both had been chemists before the lure of biology drew them to cross the double-yellow separating academic fields. Pasteur himself was a chemist and avid crystal grower when, as a consultant to the French wine industry in Strasbourg in the 1850s, his studies in fermentation led him to discover microbes: He later posed—and proved—the germ theory of disease, ushering medicine into the modern age. “Fortune,” he said famously, “favors the prepared mind.”

Boger, several years older than Schreiber and recently chartered by Merck to head his own drug design group, was making a similar transition. His renin work had catapulted him upward within Merck and attracted the attention of other chemists. Yet if renin had proved anything, it was the value of using a structural basis for designing drugs and the necessity of including protein chemistry and biology in an overall strategy that Boger himself could control. Ever since his years with Knowles, whose work with enzymes bridged several disciplines, Boger had aspired to do swarming, multidisciplinary research. But he’d never been able to act on it until now.

Between 1985 and 1987, he was given charge not only of immunologists and biologists but of protein chemists and X-ray crystallographers. Like Schreiber, he, too, was suddenly in a position to move beyond making molecules to a more open, tumultuous, and visible scientific realm. He, too, considered biology “too mushy.” (“I mean, what are the basic concepts of biology and how sure are we of them?” he would say. “Well, there aren’t any, hardly. It isn’t that the people are stupid, it’s that the data isn’t there.”) Consequently, he intended to bring it new rigor through resurgent chemistry. Though his goal was to discover drugs and Schreiber’s to use synthetic molecules as biological reagents, they were now on the same path, chasing the same objective, the same role.

Cyclosporine simultaneously focused them and brought them together. Boger saw the molecule as a jumping-off point for a program in immunosuppression, an area in which Merck was weak and which he’d inherited. “The immunology and biology groups I worked with at Rahway had all kinds of exploratory biology going. I said, ‘That’s all very interesting, but there’s nothing for me to do here. There’s something for me to do here in cyclosporine. It’s a drug.’ ” Schreiber, typically, was intrigued for another reason: “It was interesting to me from the point of view of molecular recognition . . . I wasn’t interested in the fact that this was a very useful drug.” With Merck collaborating with Yale, Boger and Schreiber—who’d known of each other since they were both at Harvard and had met during Boger’s recruiting trips to New Haven—now began seeking each other out. Not as personally fond of each other as Woodward and Tishler, they were united by something just as potent: immense, unrelenting self-interest.

Fusing Boger and Schreiber even more tightly than cyclosporine were its frustrations. Neither of them was set up to accomplish what he hoped. Boger didn’t have his own molecular biologists and so depended on Yale for protein. “We were trying to do it all by collaboration,” he says. “It wasn’t going fast enough, but I knew what I had to do.” Schreiber, meanwhile, made some molecules based on the structure of cyclosporine, but they were “doomed to failure. . . . The geometric shapes we were aiming for were all inappropriate. We needed protein chemistry.” Throughout 1986 and early 1987 Boger and Schreiber independently began not only to face the same problems, but to draw the same conclusions. Each foresaw a self-contained, interdisciplinary, structure-based research effort—a kind of project-derived institute—with himself in complete control.

Scientists, curiously, talk a lot about luck. As murderously as they work, as dedicated as they are to rigor, as much as they may believe in their own perfection, they concede that great scientific careers are almost always favored by something else: great timing or an unseen hand connecting the observer and the observed. Pasteur’s oft-used remark about fortune encapsulates the view, almost universally shared among scientists, especially in the drug industry, that they’d rather be lucky than good. The inevitable counterpoint is that it’s best to be both lucky and good.

Boger and Schreiber have been not only lucky but charmed throughout their careers. Much of what accounts for scientific good fortune is looking at the right problem, and both have a knack for positioning themselves in highly productive areas. Part of that is simple, competitive intelligence gathering, a desire to push and stay ahead. Schreiber, for instance, subscribes to a service that reviews all European patent applications, which issue ahead of those in the United States and thus are a frequent first indication of new molecules. Boger complements his own “rabid” reading by foraging widely among an array of data banks and computerized searches. Information junkies, both of them are always looking for anything to give themselves a fresh edge. Now, in mid-1987, both suddenly saw something obscure on the horizon that hit them equally with the force of a revelation: FK-506.

Like college roommates who fall in love with the same woman on the same day, each insists he noticed the molecule first—Schreiber among his European patent searches, Boger in a copy of Ochiai’s slides from the August 1986 meeting in Helsinki. Far more significant, besides such niggling, is how they understood it. They each saw, ahead of most others, a potential bonanza almost solely on the basis of the molecule’s shape. Boger: “I knew what I wasn’t looking for. I wasn’t looking for a tricycle, heterocycle ring, flat molecule with five nitrogens in it—that’s just ugly. FK-506 was a beautiful molecule. It fit everything I was looking for.” “This is too good a story to leave alone,” Schreiber told himself after noting the similarity to rapamycin. “This is too remarkable.”

Each leapt without hesitation. One obvious first question—What did FK-506 bind to?—led to the quasi-tie in discovering FKBP. Even more critical for Boger and Schreiber, given their previous frustrations, were organizational issues: personnel, lab space, reagents, logistics, deployment. Now that each knew exactly how he wanted to approach a major new molecule and had such a molecule in hand, speed became everything. Drug companies have long argued they can marshall resources quickly that academic scientists must assemble painstakingly through onerous, often messy, collaborations. Merck’s narrow victory with FKBP seemed to prove that. Yet as Boger and Schreiber began building their respective programs, the opposite seemed true: Schreiber’s incorporation of multiple disciplines into his lab, combined with Merck’s huge size and lumbering organization, seemed to favor Schreiber. “I immediately began to think how I was going to wind down cyclosporine and wind this up without having to crash cyclosporine,” recalls Boger, who for the first time began to doubt whether Merck was “set up to generate the kind of information I was going to need.”

Boger and Schreiber each now had the molecule he’d been seeking. Each knew exactly what he wanted to do and had the support of a great institution. But each still lacked what he most wanted and needed: complete control. As long as Boger remained at Merck, he would have to fight to get the people and reagents he needed when he needed them. At Yale, Schreiber would never have a broad enough group to dispense with most collaborations. In the end, the result was much the same: in Boger’s phrase, “not enough horsepower.”

Within eighteen months, each of them was gone. Schreiber leapt first. Called to Harvard by Derek Bok one morning while shaving, he quit Yale and returned to Cambridge in the fall of 1988. Four months later, Boger, enticed by Kinsella, established Vertex. Like exiled princes suddenly in power, they quickly allied themselves. Kinsella, at Boger’s insistence, recruited Schreiber for Vertex’s SAB. Schreiber, for his part, was enthralled: “I thought [Boger] was a spectacular choice. I was impressed that Kinsella was willing to aim that high.” By mid-1989, the two were aggressively playing badminton together at a backyard barbeque at Boger’s new outsized suburban Colonial and toasting an alliance that anyone familiar with the field could only find fearsome.

Drawn across the terrain of science to a common meeting place, they now stood so close that their shadows intertwined. And yet they, and seemingly everyone around them, overlooked the obvious. Boger and Schreiber had engineered a storybook collaboration—Magic Johnson and Michael Jordan in the same backcourt—but the competition between them was innate, overarching, inevitable. They had wanted the same thing and, having gotten it, soon realized that there was room for only one of them on the solitary plateau where they were heading next.

They had created—less than two miles from each other—competing programs as much like one another as they were unique from anyone else’s. Indeed, to hear Schreiber talk about his new labs—the “Schreiber Institute,” Vertex scientists called it—was eerily like listening to Boger discuss Vertex. “We can do synthetic chemistry, make molecules,” Schreiber says. “We can use those to purify receptors with the protein biochemistry effort, use molecular biology to clone the genes, overexpress the proteins. We have the genes themselves available for transfection into mammalian cells. . . .

“It’s really,” he says, “completely circular now.”

Completely circular, and a mirror image of Vertex except for one notable omission: X-ray crystallography. It was the one piece of armamentaria that Schreiber, expecting to work with Navia, had failed to include—the one imperative, Boger would say, he still hadn’t stolen.

•  •  •

Schreiber moved aggressively to bridge the gap. Having decided to pursue FKBP, he knew that he couldn’t concede the crystal structure to others, least of all to Vertex, which, despite what he thought of it, had still fired him. A high resolution X-ray structure was a necessity for anyone aspiring to broad dominance in the field. On the other hand, since Schreiber had been spurned, it wouldn’t hurt for him to have a less visible collaboration, one that wouldn’t attract the attention of the Cambridge rumor mill.

Within days of receiving Boger’s “letter bomb” discontinuing his contract, he called Jon Clardy, a highly regarded crystallographer at Cornell. He and Clardy had spoken before about the enzyme, and Clardy, who had never solved the structure of a protein before, had wanted to work on this one.

Although Schreiber’s contract with Vertex extended through the end of 1990, Schreiber and Boger were now also formally rivals. Boger, of course, knew nothing of Schreiber’s calculations. He could only guess how Schreiber would act. Indeed he had hoped that the stern language in Schreiber’s contract combined with the fact that Schreiber was still a major shareholder in Vertex would cause him to hesitate. But to think he would hold back now defied everything Boger knew about him.

Their split was total, inexorable, and resonated with more history than either of them knew. Forty years earlier Tishler and Woodward, the best academic chemist and the best drugmaker of their generation, epoch-making Harvard men, teamed up to make the most spectacular molecule of their time: cortisone. Encapsulating the most productive era in the history of drug research, they opened up new avenues not only in chemistry and drug development, but throughout medicine. Ironically, bitterly, their collaboration signaled its own demise and that of their field.

Boger’s and Schreiber’s own collaboration on FKBP had promised multiple redemptions. As heirs of Tishler’s and Woodward’s legacy, they would fulfill it by improving on perhaps the most tantalizing biological molecule since cortisone, FK-506. More, they would do it by catapulting research to its next—and perhaps ultimate—stage while reenthroning chemistry at its core. Yet this was a different age. Just as cortisone and the other triumphs of the 1940s and early 1950s produced a high-water mark for collaborative research, they also set in motion—ironically, by providing the world with powerful new molecules—an entrepreneurial era in science that made collaboration more and more difficult. Competition now ruled and overruled. Ideas of fraternal vengeance, of sons atoning for fathers, of bringing history full circle, were subsumed by the exigencies of winning.

Now that their collaboration was dead, Schreiber had less trouble than Boger dissecting their shadows. His prominence in immunophilins, plus the natural tendency—and need—for academics to be recognized, had always given him a higher profile. Starzl, for instance, with whom Schreiber also now began collaborating, thought Vertex was “Schreiber’s company”—a not uncommon understanding. Schreiber had clearly never needed Vertex as it had needed him, and though Boger would say the company’s interest was purely in Schreiber’s marquee value, Schreiber believed it was Boger’s wounded ego that forced their estrangement. “With young start-up companies,” Schreiber would say, “it’s very important that they establish their own identities.” He dismissed the suggestion that what Boger and the scientists considered his inability to keep quiet about the company’s secrets had anything to do with it.

Freed in his mind, if not contractually, from any further obligation to the company, Schreiber swiftly rededicated himself. “Science is all that matters,” he said cooly. “They got themselves in this situation by getting into in a very competitive area.

“I just hope they didn’t think that anyone would ever slow down for them.”