Boston’s World Trade Center, unlike New York’s, is not a beacon of wealth and power but a refitted waterfront mercantile mart. It sits on a pier asquat the city’s famously ruined harbor and has a postcard view of downtown, which, after the harshest winter in decades, shimmered this brilliant Wednesday morning like an aurora borealis. Two months earlier, the World Trade Center in Manhattan rumbled and shook as a car bomb blasted a crater in the underground parking garage of the Vista Hotel, where in 1989 Boger had taken his manifesto to Wall Street. Now, in Boston, he faced 250 worried members of the Massachusetts Biotechnology Council, waiting to proclaim—not unpleasurably, for he had predicted this, too, and was confident Vertex would prevail—a day of reckoning.

Seldom had an industry’s fortunes fallen so fast. In just eighteen months since the biotech bubble of 1991 finally burst amid a string of spectacular flameouts, all drug stocks, big and small, had lost almost half their value. Worse—far worse, many in the room believed—the drug industry’s long-standing expectation of limitless profits had become a ripe political target. The Clinton administration, as one drug-industry lobbyist put it, had calculated that the best way to win its health care reforms was to “go to war” with the drug industry. Hillary Rodham Clinton’s task force was talking ominously about cutting at its heart, with price controls. Without the specter of enormous profits, stocks could only go lower, investors would flee, capital would dry up, innovation would flag, companies would die. Despite its extraordinary successes, high-risk research, the presumptive justification for all those profits, was beseiged, demonized, as perhaps no other time in its history.

Saying he expected “to see frogs raining down from the sky sometime soon,” Boger told the assembled executives that only the smartest, fleetest, most adaptable companies—companies like Vertex that were burning tens, hundreds of millions of dollars in pursuit of fast, novel drugs for big markets—would compete successfully in the new period. Why only them? “We’re more motivated,” Boger said, “and the fear of death and God is closer to us.” Since all drug firms were likely to be deprived of two of their three main avenues for making money—raising prices and developing copycat “me-too” drugs—there was little denying Boger’s analysis. Highly focused innovation, backed by a feral organizational leanness, was now key. Gregariously, Boger ended with a slide of a cartoon showing a drug company executive talking to a scientist. “I like it,” the caption read. “Find a disease for it.”

Boger could afford this bit of light heresy. Despite the hard uncertainties besetting the industry, Vertex’s outlook couldn’t have been much brighter. Two weeks earlier, the company had signed a $20 million deal with Kissei Pharmaceuticals, the fastest growing drug company in Japan, to develop and market an AIDS drug in Japan and the People’s Republic of China—a drug that Vertex now was within weeks of selecting from several strong candidates. (Kissei’s ceremonial gift was a framed photograph of Mount Fuji, just as Chugai’s had been.) Another leading company had declared a “special urgency” to license the compound in the United States and Europe, and hadn’t balked when Boger and Aldrich floated a trial balloon for a $100 million deal. Meanwhile, barely twenty months after being blindsided by calcineurin, Vertex had two other near-clinical candidates rapidly under development, one of them a stepchild of the hard-pressed immunophilins program. Within 110 people, nearly $50 million in the bank, a new subsidiary based on Navia’s enzyme work, and a relatively buoyant stock price, Vertex had outshone even Boger’s most aggressive predictions.

The conference itself, formally an annual meeting of a statewide trade group, affirmed Boger’s new power and influence. Not only had he been asked to provide the industry’s perspective but Vertex’s stamp was everywhere on the proceedings. Brochure covers featured Moore’s FKBP-12 structure and the company’s crystal structures of HIV protease done up in Dali-esque portrayal. The meeting’s major scientific section was on structure-based design and resembled a Vertex road show. Chemistry and biophysics were whispered about with new reverence. In the aggregate, the meeting seemed a coronation, a concession that the future lay not in drugs that were proteins but in those that inhibited them—just as Boger had long said.

Of course, respect within the biotech industry had never been Boger’s main goal or even a major one; he was out to shake up the big drug companies, particularly Merck. Here, too, a reversal of fortune gave him ready satisfaction. The keynote speaker was Ed Scolnick, Merck’s brilliant and tempestuous director of research and Boger’s chief sponsor at Rahway. It had been Scolnick who had told a Harvard Medical School audience three years earlier that having the structure of HIV protease had given the company “some help, not dramatic help” in designing drugs. Now, with Murcko, who had talked dazzlingly about Vertex’s design program in HIV, seated next to him on the dais, Scolnick issued a staunch and—given the audience—surprising defense of Proscar, Merck’s drug for shrinking prostates. With Merck’s market capitalization off a staggering $20 billion in the past year due in no small part to Proscar’s disappointing debut, Scolnick’s investment-style sales talk indicated that even the industry’s titans were now having to stoop. Boger thought the talk “bizarre.” He beamed when a few days later he received a hand-written letter from Scolnick, congratulating him on his apparent success.

Roaring into adolescence, Vertex had in four years come of age by every measure but the one that mattered most; it still had no drug.

•  •  •

In fact, it was tantalizingly close to having as many as three. As was typical of Boger and science, luck—and the ability to capitalize on it aggressively—had been instrumental in at least a couple of them. Hair-raising reversals had been the norm.

After the initial demonstration of structure-based design with its first semaphore compound, 367, Vertex’s immunophilins project bogged down in the implications of Schreiber’s and Weissman’s calcineurin work. Nothing the chemists made came close to FK-506, which was proving in European clinical trials to be as effective as but significantly more toxic than Starzl had said and which Merck, Sandoz, and other companies were finding impossible to improve simply by altering its structure. Then, remarkably, chemist Jeff Saunders made a compound that was highly immunosuppressive, bound tightly to FKBP-12, yet seemed to work through another channel, avoiding the quagmire of calcineurin entirely. For seven months the chemists toiled almost exclusively at optimizing Saunders’s molecule only to discover it a false miracle, the result of what Boger would call (with uncharacteristic melodrama) a “diabolically misleading” cell assay that had been born out by animal experiments that turned “mysteriously negative” soon after the initial assay was found to be in error. Distraught, beleaguered, they returned in the summer of 1992 to Murcko’s “nightmare of terror”—trying to block calcineurin, for which they still had no structure and little hope of getting one soon.

It was a grim time. Yamashita, making good on his promise, left Vertex in July 1991 to go to medical school in Hawaii. He moved in with his parents, leaving Vertex briefly with half its bench effort in crystallography and with many of the scientists believing he’d have stayed if Boger had instructed Navia to give him his own project. Boger refused to do so. Navia, meanwhile, began traveling nearly full time to promote his enzyme technology, which would soon engender new labs and a new entity, Altus Biologics, Inc., Vertex’s first subsidiary. Murcko, deprived of data both in immunophilins and HIV protease, again became agitated, complaining bitterly about what he considered the company’s faltering commitment to structure-based design. Morale sank as the project councils stumbled and lost their footing.

Vertex had raised another $25 million by selling more stock during the final days of the bubble the previous fall, but it had been nearly two years since the deal with Chugai, which was becoming impatient. The company’s burn rate had climbed to $7 million per year, and Boger had begun preparing the board for “double digit losses”—$10 million or more. Where it would turn for funding next, no one, not even Boger, could say. Of Wall Street’s renewed iciness, he said, “You couldn’t sell hair tonic that gave eternal life right now.”

For a time Vertex appeared to have a promising lead in HIV protease, but at a conference in August 1992, chemist Roger Tung learned that the compound class was stuck squarely behind another company’s patent. Tung spent the next twenty-four hours in his hotel room, despairing and furiously sketching new molecules. By fall, Vertex seemed for the first time in its brief history to be adrift, with no clear path to the next stage.

Boger, as ever, remained confident, but he also knew that changes were necessary. Vertex had gotten too big for him to be all places at once, all things to all people. Quietly, he began recruiting Vicki Sato, head of research at Biogen, Aldrich’s first firm, to oversee the company’s science. It was an admission that the demands of chasing money had overwhelmed his ability to do active science and that his ultimate role, in a world dictated by business, was (to use an overused word) in “growing” the company. Boger retained final control of the projects and continued to be their driving force, but Sato, a quick, street-smart no-nonsense former biology professor at Harvard would be the company’s field commander, the person responsible for keeping it on track and on time. Boger hired her, he said, in part to make peace with the company’s biologists, many of whom still distrusted him over calcineurin.

Within months, Sato reorganized Vertex’s project councils. She named project heads—Dave Armistead in immunophilins, Roger Tung in HIV protease, Dave Livingston in a new project in inflammation, and Matt Harding in a new anticancer program. Because there weren’t enough of the positions to go around, Boger simultaneously named Thomson, Harding, Murcko, Livingston, and Debra Peattie as senior scientists, a rank previously held only by Navia. Repudiating the flat organizational structure of Boger’s social experiment, Boger and Sato felt the moves were necessary to keep several people from quitting the company. Boger’s first hires had now been with him almost four years. Their founders’ stock would soon be fully vested, and they would be free of the “golden handcuffs” that risk-taking young companies use to keep people from leaving. Headhunters were calling the scientists more and more frequently. Reluctantly—regretfully, it seemed—Boger acknowledged that the scientists would need conventional rewards like titles and status to satisfy their ambitions and the imperatives of their careers.

With hierarchy came new stresses—Saunders now reported, for instance, to his friend, nemesis, and former labmate Armistead, who no longer ran reactions but spent his days in meetings, riding herd. Immunologist Patsi Nelson left the company rather than report to Harding, with whom she considered herself professionally equal. Competitive preening among the scientists exposed jealousies previously without outlet. Thomson, whose group arguably had produced more value for the company than any other, resented being promoted with people whom he considered less productive and committed to the company than himself. “Like graduating with the class,” he called it.

Still, few longed for a return to the open-ended egalitarianism of Boger’s social experiment. Boger considered that experiment a success, for it had produced the champions, the leaders, who would become Vertex’s new scientific cadre. But most others welcomed the change. Quietly, the company made the transit to a more conventional management structure without smothering itself, as other brash start-ups often did. By the end of the year, Vertex resembled more closely other companies at its stage, a place with a ladder and individuals elbowing to climb it at every rung.

Boger was less disappointed than he seemed. He had gotten what he wanted—self-selected leaders and a sense among almost all of the scientists that their ideas were valued and would be heard. As with most concepts, egalitarianism was for him a tool, not a goal. What he believed in was equal opportunity, not equality of status. The ranks had held. Among senior researchers, only Patsi Nelson had left.

•  •  •

On June 28, 1992, doctors in Pittsburgh transplanted a baboon liver into a thirty-five-year-old man dying from hepatitis B. There were twenty-seven people in the operating room, including ten surgeons. Starzl didn’t direct the experiment himself but had authorized it to address a desperate shortage of human organs: a shortage, ironically, that resulted from Starzl’s success with making liver grafts standard therapy and that had left Pittsburgh with half as many livers as patients and a dangerous amount of what economists call “surplus capacity.” Using FK-506, doctors kept the man alive for seventy days. He died of a stroke and massive infection, his unrejected liver still functioning. Later in the year, the group transplanted five organs—pancreas, liver, stomach, large and small intestines—into a four-year-old girl. In January, they repeated the baboon experiment, then cancelled the program.

Starzl, dauntless as ever, pressed ahead with the urgency of someone half his age. His transition to immunologist was now all but complete, if not yet accepted by those who studied the body’s defenses at their atomic level. But he was to be no gray eminence. Typically, he was determined to prove them wrong. In 1992, he began publishing a series of articles—a unified theory, so to speak—of graft acceptance. He now believed that when a body received an organ graft it became a chimera, a mixed being, a hybrid of host and donor. Cells from the transplanted organ migrated throughout the body while those of the recipient invaded the alien tissue. What immunosuppressive drugs did, he hypothesized, was protect the cells of each from the other, causing a “biological truce,” an equilibrium of crossed souls. Unproven, the theory would ultimately explain both transplantation and autoimmune disease, he insisted. Coming upon it had been the apotheosis of his long career. “A glimpse of eternity,” he rhapsodized, and a “fair trade for the thirty-five years of work preceeding it.”

Proportionately, Starzl’s contributions with FK-506 waned as the field around him exploded. He still flooded the FDA with requests to launch new clinical trials, especially with autoimmune diseases, but there were others now with more experience and insight to advance the drug’s human experimentation. Brain researchers, for instance, now thought the drug might treat strokes. Weissman’s and Schreiber’s calcineurin discovery had invited new realms of thought, new interpretations of old mechanisms, and the interest of the world-class researchers throughout medicine. By mid-1993, it appeared that FK-506 would finally be approved by the FDA, probably by the end of the year. Starzl, who had salvaged the drug seven years earlier when it was rotting the guts out of dogs, was systematically evaluating new compounds at the time, looking ahead.

•  •  •

Mary Arthur, the Louisville teenager who was the first patient to receive transplanted islet cells and whose cancer preoccupied Pittsburgh surgeon Andy Tzakis during the FK-506 conference in Pittsburgh, survived the surgery to her jaw without disfigurement. Cancer-free three and a half years after her transplant, she was still producing her own insulin. She planned to get married. After considering a career as a chef, she switched her college major to pharmacy.

•  •  •

Schreiber charged ahead brilliantly, if less ecstatically. Determined to control the burgeoning field of immunophilins research, he continued to work seven days a week. But as his influence and visibility grew, so did his burdens. Still shy of his fortieth birthday, he began complaining of the relentlessness of science, how it drove you to be first, then pitilessly gave no pause before the next race. He sounded at times like a man strapped to a mast. “The world would be a lot better place,” he said mordantly in the fall of 1992, “if there were no scientific prizes.”

He had become “almost a caricature” of the obsession with individual credit that was both science’s driving force and the source of much of its bitterness, a former collaborator said. Yet his determination remained immense. He was reshaping science, just as he planned. Biologists still dismissed him as a revisionist chemist, chemists as an apostate and amateur biologist. But they couldn’t dismiss what he had done. Perhaps as much as any of them, he and his colleagues had elucidated the basic mechanisms of how cells communicate internally. By May of 1993, he had stopped referring to the “black-box” of signal transduction. He believed the problem had been cracked.

The signal transduction company that he and Kevin Kinsella had originated, Ariad Pharmaceuticals, opened six blocks from Vertex in an MIT-sponsored Research and Development park, and Schreiber consulted there approximately one day a week at a starting salary of $75,000. Meanwhile, he amassed a freezerful of natural molecules that, like cyclosporine and FK-506, had intriguing biological effects, banking them like so many sperm samples. With enough compounds in the bank to seed “more research projects than I’ll be able to study in my lifetime,” he swung headlong toward the next frontier—gene therapy—developing a method for switching transfected genes on and off. By summer, he was negotiating with venture capitalists to start a new company.

•  •  •

Vertex’s problems in immunophilins taunted the scientists acutely. Thanks to Yamashita, who determined the right crystallization conditions in the weeks before he left, the company was now generating every few weeks an X-ray structure of FKBP-12 with a different Vertex compound bound inside the protein. But without a calcineurin structure, they remained lost. When it turned out ultimately that they and Schreiber had both been right—that FK-506 worked through an effector region and by changing the outer shape of FKBP-12—it only reminded them how forbidding a task they faced. Not only did they need to move too many atoms in too many places, but even if they did, they would still be trying to block an enzyme so biologically vital that it might seem a nightmarish target for a drug.

More and more, the chemists felt they were beating a dead horse. They were doing structure-based drug design but on a project for which that still might not be enough.

•  •  •

It was Boger who found the pony.

Cyclosporine had been known to switch off a mechanism in cells that enables them to expunge toxins. Like a micromolecular bilge pump, the process, known as multidrug resistance (MDR), had long frustrated oncologists, who watched helplessly as they infused powerful cell-killing agents into their patients only to see them flushed into the blood and carried off.

Boger speculated that Vertex’s semaphore compound, 367, because it bound to FKBP-12 but wasn’t strongly immunosuppressive, might block MDR as effectively as cyclosporine but without cyclosporine’s prohibitive side effects. Presumably, it would let doctors get more cytotoxins to more cells and thus save more lives. Boger suggested the idea to Harding in the winter of 1991, and it was soon given further credence by an article suggesting that FK-506 also blocked MDR, though very weakly.

Harding sent 367 and several other compounds to Yale for testing. The molecule looked extremely promising. Suddenly Vertex had a lead in a virgin market worth up to $500 million. By early 1993, less than eighteen months after Boger’s initial insight, the company had chosen a derivative of the molecule to begin developing for human experiments.

Far from the orderly, data-based process of iteration and reiteration, the selection of Vertex’s first clinical candidate illustrated another Vertex dictum: The ultimate reward for research may turn up elsewhere than intended. The key is to draw the right lessons, be astute, act decisively, do the proper experiments.

Within weeks, Vertex was pursuing a deal to license the rights to a possible second clinical candidate—a promising treatment for sickle cell anemia—snatching it from under the nose of a top European drug company.

•  •  •

Gratification suffused the Vertex conference room like a glow. In an unambiguous display of the speed and effectiveness of the company’s “feedback loop,” as Murcko called it, crystallographer Eunice Kim was presenting a new structure of a strikingly potent HIV protease inhibitor. For months, as the chemists had churned out better and better molecules, becoming steadily more excited, Kim had been reducing her turnaround times for feeding them detailed images of how the compounds bound atom by atom within the enzyme. This one, 328, had taken her exactly five days from the time she got the molecule. (Yamashita’s ill-fated structure of FKBP-12, by comparison, had taken more than a year.)

“What took you so long?” Boger said admiringly.

“Where’s 330?” joked Sato. She was referring to a molecule submitted within the last week that was five times less potent but that had looked spectacular in its ability to survive the gut and remain intact within the blood. It was the inability to last in the body long enough to work, of course, that doomed almost all of the best protease blockers, and 330’s bioavailability had been deliberately engineered into the molecule using Kim’s structures. The compound differed from an earlier one in its series by the repositioning of two carbon atoms within a binding pocket measured in billionths of meters. Vertex could spare the loss of potency: for sheer binding, its most potent molecules were now so perfectly designed that they were off-scale in the company’s assays.

Six compounds in all were still in contention as Vertex now set about choosing which one to scale up for human testing—an enormously complex and expensive process requiring quantum jumps in activity at every level of the company—but as Boger had been pressuring for months, the project council was running out of time. It needed to “pull the trigger.” Tung, cautious as always, importuned for more data. In three weeks he would be leading a contingent of six Vertex scientists to the massive annual AIDS conference in Berlin, there to disclose the company’s work publicly. He wanted to tell a complete story.

Boger grew impatient. “I’m all for stalking horses,” he said, “but when the real horse is ready, I don’t want to keep him in the paddock because the stalking horse is at the last turn and we want to let him finish so that he doesn’t feel bad. I want to go out and shoot him.”

To Boger there was only one issue: getting the FDA to approve the testing of Vertex’s compound in humans before Merck’s protease blocker, announced in February, was licensed. He had been surprised that Merck’s compound, which he conceded looked impressive, wasn’t a “killer molecule” and had guessed that the company had rushed it into the clinic so that it might be on the market by the time CEO Roy Vagelos retired in November 1994. Boger believed that Vertex had the better drug—smaller, easier to synthesize, more likely to get into the brain, which is protected by a chemical filter and which harbors the virus. But if Merck’s drug was already on the market, all bets were off. No one dominated competitive markets better than Merck. Worse, Boger half feared that Merck would simply give its drug away, as it had with its cure for African river blindness, in return for a huge tax break and a mountain of glowing press. At the very least, Merck’s drug would set the standard for approval for everyone else.

“The rest of the world is rushing headlong,” Navia said. “The other guy can have an order of magnitude shittier structure, but if you’re number 2, you’re fucked.”

“Throw a dart,” Sato urged.

After a few minutes, the decision was made. Vertex would proceed with the development of 330, changing course only if new data arose to indicate that it had something better.

It was done. Navia’s “hallucination” and Tung’s embrace of it to escape Armistead’s dominance in chemistry; Boger’s searing antialtruism and obsession with beating Merck; Vertex’s calculation to go into AIDS because it was the quickest route to profitability; its use of the program to sell the IPO—more deliberate origins and higher motives were easily imaginable. And yet not to Boger. For him, lofty motives were infinitely less powerful, less trustworthy, less useful, than pure ones. Science was too difficult for people to engage in solely because, as he had written at age thirteen, they wanted “to help rid man of the burden of disease . . . and to help man get along with man.” They did it because they were absolutely certain it could be done, and to prove to themselves and the world that they could do it first. They did it to bash their competitors, to think themselves divine, to win, and to avoid the terrible, deathly anguish of losing. Backbreaking science and unblemished greed and raw fear, not moral correctness, would conquer AIDS. Boger was absolutely sure of that. He didn’t want to save the world. He wanted to control it; he believed he always had. Now the world would see the fruits of that fierce presumption.

He wasted no time. Dispatching most of the scientists from the room with a hail of laughter that was part congratulation, part triumph, and all, in its unalloyed arrogance, roisterously appealing and charismatic, he huddled quickly with Tung, Sato, and Livingston to attack the next set of experiments—toxicological studies, animal studies, multidrug studies with other compounds, one-on-one comparison studies, formulation studies to determine how to deliver the drug, blood assays, ultra-pure large-scale preparations of the molecule; studies of the compound in several kinds of animals and every type of cell, at every temperature and pH imaginable, over short periods and long periods, in duplicate, triplicate, and with every conceivable risk and ambiguity addressed. By Vertex’s timelines, the molecule had to be available for human experimentation in AIDS patients by the end of the year or during the first quarter of 1994. An immense amount had to be known about it before that time; more, immeasurably more, after.

As one Merck veteran much admired by Boger would say: “There are those who make the case that finding lead molecules is the easy part. Making drugs is hard.”

•  •  •

The following day, May 20, John Thomson flew home to Australia for his first visit in four years. His parents were ill, he was eager to see his children, and he had to apply in person for a visa to go to Berlin. It had been Thomson who had again, through sheer force of will, enabled Vertex, after struggling for almost two years, to produce so much HIV-protease that the need for crystals of it was no longer an impediment. He had also isolated and crystallized a highly scarce and extremely competitive protein that was to be Vertex’s next target.

His labors, anointed with these and other successes, had taken him through a passage. He was still driven, but no longer by anger. His self-respect had returned and with it his respect for others. His drinking and smoking were down to levels appropriate to someone who imagined for himself a future. His group had grown to eleven people, and with more pride than he would concede, he accepted—because he needed it, he emphasized, not because he wanted it—a small, windowless office. On the day before he left, he wrote a check for a terrifyingly sleek new motorcycle. “A rocket,” he called it, laughing self-knowingly in a way that made it seem as if what interested him was simply the pleasure of going faster than before.

•  •  •

It was Vertex’s work on HIV that rescued the company from the vagaries of immunosuppression and propelled it to the next tier.

Climaxing two years of maneuvering—two years during which the immunophilins project foundered and when hopes for conquering AIDS looked increasingly dim—Vertex announced that it would develop its lead protease inhibitor jointly with Burroughs Wellcome, the British-owned drugmaker and manufacturer of AZT. The molecule was not 330 but a second-generation compound, VX-478. The deal, which would eventually bring Vertex $42 million, was in fact worth several times that since Wellcome would pay the full cost of development—perhaps as much as $200 million. Vertex’s stock rose $2 on the news, to $17.50.

It had been Wellcome, of course, that had led the drug industry into AIDS, and Boger was mindful of what had followed. Ever since the company first introduced AZT during the mid-1980s, it had been besieged and vilified. AIDS activists had organized around-the-clock picketing at the company’s North Carolina headquarters and had breached security at the New York Stock Exchange to chant “Sell Wellcome!” and “Fuck drug profiteers!” For nearly a decade, the firm had been mired in costly lawsuits that threatened its patent position and, ultimately, more than $500 million a year in revenues. So onerous was the specter of such well-publicized controversies to a small firm that Boger and Aldrich had initially resisted going into AIDS research largely because of it.

Boger was pleased to be allied with the drug company that knew more about AIDS than any other, yet in such a way (Wellcome now owned the North American and European rights to the drug and would pay royalties to Vertex) that sharply diminished Vertex’s own exposure. “I’m glad our money comes off the top,” he said.

Boger’s satisfaction was equalled, clearly, by Wellcome’s own relief at having lined up a potential successor to AZT. Six months earlier, a study in Europe showed that the drug did nothing to prolong the lives of people with AIDS, despite slightly delaying the onset of symptoms. More recently, a Harvard study concluded that even the drug’s minimal benefits were often cancelled out by its side effects. Accompanying nausea, vomiting, and fatigue made taking AZT not worth the trade-off of delaying the advent of fullblown AIDS for many patients. AZT did have therapeutic value; it seemed to protect the fetuses of women infected with HIV and apparently kept many people with AIDS from becoming demented. But the consensus, as the Times reported, was that it was a “moderately useful drug that can slow the course of AIDS in some patients for a limited period of time.” Nevertheless, with AZT accounting for almost 15 percent of Wellcome’s income, the company was hardly going to walk away from the one truly lucrative franchise in the AIDS market.

AZT, by default, remained the drug of choice for people infected with HIV, but frustrations with the compound—and with the vast scientific effort that had failed for nearly eight years to replace it with something better—had grown huge. Thirteen years into the epidemic, hope seemed to be running out. In November, prospects seemed to reach a new low when an entire battery of experimental vaccines—vaccines that had been highly effective against laboratory strains of HIV—was wiped out in tests against strains of the virus taken from people. Not one showed the slightest efficacy.

Boger, typically, was undismayed by the failures. He considered them less a result of complex biology and a wily virus than of misguided and misapplied science. Much of his confidence, as always, was based on Vertex’s choice of target. Several other companies had now shown that blocking HIV protease remained the best hope for stopping the virus from spreading. The latest, and perhaps most enthusiastic, of these was Merck. For several months, blood tests of four patients who were given Merck’s protease blocker showed dramatically reduced levels of virus. In this one admittedly limited field trial, the compound seemed to slow the spread of HIV better than any drug yet devised.

Not only was Boger confident that Vertex could beat Merck’s drug, he was sure it could generate even better ones through structure-based design. A week earlier he’d sought to prove the point at an AIDS meeting in Washington. For months, Vertex had been trying to get enough of Merck’s compound to begin comparison tests with VX-478—a competitive necessity for any company hoping to position a new drug. Having finally made enough of the molecule to determine how it bound to enzyme—how it worked atom by atom—Vertex chemist Dave Deininger had given a sample to crystallographer Eunice Kim, who promptly solved the structure of the complex. At the meeting, after Merck’s scientists conceded they didn’t know how their compound worked specifically at a molecular level, Boger, at the podium, concluded his own talk with a slide showing how Merck’s drug sat in the active site of the protease, in effect answering the question for them. (Without a guarantee of patent protection, Boger refused to disclose the structure of Vertex’s own molecule.)

Several leading drug companies were now developing protease blockers—Merck, Roche, Abbott, and Merck-DuPont. Agouron, the early structure-based design company long dismissed by Boger, had such a molecule, as did Searle, the Monsanto subsidiary whose patent disclosure had temporarily derailed Vertex’s chemistry effort when Tung had learned about it in 1992.

Most of the others were ahead of Vertex and Burroughs in getting their drugs into the clinic, and the competition—for attention on Wall Street, for scientific recognition, for clinical investigators, even for patients—was extreme.

None of this stayed Boger’s enthusiasm, which was typically unbridled. First and most encouragingly, he had Vertex’s compound, which, while not as potent as some of the others, had several extraordinary properties. Unlike most protease inhibitors, it wasn’t easily cleaved; even when delivered orally, it remained in the bloodstream at high concentrations for several hours, meaning that it would provide what many of the other drugs couldn’t—constant protection at acceptable doses. In test animals ranging from rats to primates, it was practically nontoxic, so much so that the only side effect that the company had been able to induce with megadoses of the drug in rats was to clog their intestines. And it was cheap and easy to synthesize, taking roughly seven chemical steps compared to Merck’s twenty-one. As Boger would point out, in the calculus of drugmaking, where yields decrease, often dramatically, with each step, VX-478 was “much more than three times” easier to make than Merck’s compound.

Without clinical trials to prove that the drug worked, these advantages were speculative at best. But as Vertex moved toward human testing, the next and most critical phase of its development, it had a formidable partner in Burroughs, the world’s pioneering antiviral company. This was the other cornerstone of Boger’s optimism. It had become by now an article of faith that HIV was too mutable to be stopped by a single compound. Multidrug therapies were now considered essential; indeed, the hottest story of the year in AIDS research involved the use of three drugs to cripple the virus. Given that any multidrug regimen must include, at least for the time being, AZT, and that no company knew how to work with AZT and other antiviral agents as well as Wellcome, the alliance gave Vertex a critical edge.

(This headiness persisted throughout the coming months, even after Merck was forced to announce in March that it was discontinuing its clinical trial. The company had found that viral levels in those patients taking its compound had eventually returned more or less to where they had been before treatment—suggesting that HIV had mutated yet again into a new drug-resistant strain. AIDS patients, the scientific community, and Wall Street were dismayed by the news. Institutional investors, interpreting Merck’s difficulties as a failure of protease blockers in general, punished those companies, including Vertex, that had a stake in them. Boger and Wellcome scoffed at Merck’s disappointment. They attributed it to weaknesses both in its compound, which wasn’t as long lasting as VX-478 and thus gave the virus a period of time to regroup and evade, and its clinical trial, which sought to test the drug alone rather than in concert with other drugs.)

Boger and Aldrich had always believed that the time to raise money on Wall Street was not when you had to but when you could. Clearly now was such a time. The day after the announcement, on Dec. 17, Vertex filed a fast-track stock offering that would yield, six weeks later, another $62 million. Though it was a volatile period for drug and biotech stocks, the offering built from start to finish. The company’s stock traded at $16 on the day in mid-January when Boger and Aldrich started their road show in Europe and $18 when they returned to the East Coast two weeks later. It still would be years before Vertex might have a drug. But with three deals in 1993 alone, it was now in the black, showing a year-end profit of more than $2 million. It had salved its burn rate and put $120 million in the bank. By the measure that distinguishes most new companies—penury—Vertex at age five was no longer a start-up.

Internally, the passage was marked in several ways. The company added two senior drug industry executives to the venture capitalists on its board of directors: Donald Conklin, president of Schering Plough Pharmaceuticals, and Barry Bloom, an MIT-trained chemist and recently retired head of research and development at Pfizer. It issued hefty stock options to most of the original scientists to keep them from defecting to other companies. Aldrich was promoted to Senior Vice President, by title and in fact the second most important person in the company. In a press release announcing the move, Boger credited him generously with playing a “major role in Vertex’s success.”

•  •  •

With six projects and 135 employees sprawled among five buildings, Vertex no longer resembled its fragmentary beginnings. It was sturdier now, more evolved. The original SAB, with the exception of Jeremy Knowles (now dean of faculty at Harvard) and Steve Burakoff, was long gone. Of the ten scientists first hired by Boger, all but Debra Peattie, who’d left to attend Harvard Business School and to have a baby, remained, although fewer and fewer of them at the bench. Harding, Tung, Armistead, and Livingston were now project heads, Vertex’s equivalent of middle managers. So was Thomson, who had been tapped to direct the company’s efforts against Hepatitis C yet who occasionally still worked through the night purifying protein and, it would seem, himself. Ironically, only Navia, recently becoming a father for the first time and refocusing some of his priorities, spent more time in the lab than he used to.

In mid-April, after more than five years of human experimentation, the FDA finally approved Fujisawa’s application to market FK-506 in the United States. Although licensing of the drug, now called Prograf, was relatively quick following a unanimous recommendation by an advisory panel, the clinical consensus was that it was equivalent to cyclosporine but no safer or more effective. Indeed, Starzl’s early claims notwithstanding, and as Schreiber’s calcineurin discovery would suggest, the drugs are more alike than they are different. The point was reinforced two months later when a 15-year-old liver transplant patient, complaining of severe headaches and leg and back pain, made news by declaring that he would rather die than suffer anymore from Prograf’s side effects.

Long anticipated, the approval confronted Vertex with a painful choice. The company had tuned itself up on FK-506. It had mastered the processes of structure-based design by mimicking every part of the molecule. But it was now at least five years behind a drug it could no longer say, with any reasonable certainty, that it could beat. Meanwhile, times had changed: as Boger put it, “The moment has passed when an improved FK-506 is what the world’s been waiting for.” There were now other experimental immunosuppressants, with other targets, that looked more promising. Sticking with its original strategy could only take Vertex further out of the race.

If it had been up to Vertex alone, it is likely that the company would have dropped FKBP-12 and calcineurin in favor of other, more productive targets; it would have conceded the problems in immunophilins and gone on. But Chugai had, somewhat inexplicably, became even more enthusiastic about the project the longer it went on. This left Vertex in an obvious quandary. Boger was too irrepressible an optimist to believe that the program had been anything less than a success. “But for biology,” he said, “we did a fantastic job.” But it was a success that was draining the company. Not wanting to displease Chugai, which had been more than patient, he and the scientists resolved to keep going at least until Chugai’s financial support ran out in early 1995.

All research-based companies, of course, encounter such blind alleys. One fortunate consequence of being secure financially while having several projects in development was that Vertex was now in a position to cut its losses sooner rather than later; it could afford to be truer both to its science and to investors. To Aldrich, this meant not having to prop up less-than-desirable drug candidates. More and more biotech companies, confronted simultaneously with onerous burn rates, disappointing clinical results, slender portfolios, and an ongoing drought on Wall Street, now seemed to be pursuing questionable therapies longer and longer in the face of ambiguous or even negative clinical data. Such desperation, Aldrich thought, inflated expectations ruinously, making the fall that much harder when it came.

Indeed, if there was a recurring image now within the industry, one that made investors fittingly wary of all biotech stocks, it was the slow-motion crash-and-burn of the formerly hot start-up. Such a well-publicized crack-up had recently taken place, and it reminded Aldrich and everyone else at Vertex of the price that all drug companies, particularly unprofitable ones, pay for sticking too long with a loser. Regeneron, whose $99 million IPO had signalled the crest of the 1991 biotech frenzy when Vertex went public, had gone into a death spiral with its lead drug candidate, a therapy for Lou Gehrig’s disease. The company had known the drug had serious side effects since it first began testing it in mice years earlier. When rumors of similar toxicity in humans finally forced it to revise its clinical trials in March, its stock sank immediately by a third, to $8.75. (It had gone out at $22). Two months later, when Regeneron announced it was finally abandoning the trial, its stock plunged again to just over $4.

Whether such a fall awaited Vertex only time would tell. One of the luxuries of not having a drug in clinic was that a company’s expectations couldn’t be sullied by impartial evaluation. For that reason, Boger and Aldrich took no joy in Regeneron’s unraveling, though they’d long predicted it. Indeed, their own attempts to manage expectations were about to grow much dicier.

Vertex now had four compounds in or near the clinic. Two of those were for blood diseases—sickle cell anemia and beta thalassemia. The molecules hadn’t been invented by the company’s scientists but rather had been licensed in, which, while not inconsistent with Boger and Aldrich’s original business strategy (“Vertex didn’t get founded to prove a principle,” Boger would say, “we’re trying to put drugs on the market”), did little to advance Vertex’s claim as an avatar of structure-based design. A third treatment, for cancer, was the found pony of the immunophilins project. The company’s entry in the suddenly hot field of attacking multidrug resistance—a similar molecule was now the major product hope in Sandoz’s pipeline—it too reflected perhaps more of Vertex’s savvy opportunism and marketing gamesmanship than its well-advertised scientific prowess. And while the drug appeared promising, it didn’t have the superior profile that Boger had long predicted for the company’s molecules. “The therapeutic index [the ratio of efficacy to toxicity that is the primary measure of a drug’s effectiveness] is not what I want it to be,” Boger said. “It’s not VX-478, where you can serve it up on hamburger buns.”

That left VX-478 to shoulder Vertex’s claims. “We know what we want to do,” Aldrich said in June, “We want to build the greatest drug discovery company in the world, we want to develop innovative therapies, and we want to make a lot of money for ourselves and our shareholders.” Now, in the summer of 1994, it was within the once-taboo realm of AIDS that those aspirations were finally to be tested.

For more than a year Vertex had withheld the compound’s structure, meaning that the scientific world had heard a familiar, and decidedly partial, story—great pre-clinical data, phantom information on how and why the molecule worked. Deservedly, the posture invited much skepticism. In Berlin, where the public rollout of Vertex’s AIDS program had first begun, Tung was chastised for the omission. “At a meeting like [the international AIDS conference,]” a frustrated researcher with connections to a rival company had complained, “it’s useless and a waste of time without a chemical structure.”

Now Vertex could afford no such secrecy. In June, kicking off what Boger would call “a real major scientific publicity blitz,” Tung traveled again to an AIDS conference in Europe—the first of several such appearances scheduled throughout the summer and into the fall. Boger knew that before Vertex and Wellcome could sell an AIDS drug to people infected with HIV, they first had to sell it to those clinical investigators whose patients are the first to take experimental drugs and whose support is thus essential. Like Starzl, these doctors care less how a drug works than that it does work and that they have the opportunity, exclusive if possible, to prove it. Disclosing the chemical structure of VX-478 for the first time to such a group in Nice, Tung was met, inevitably, with the first real criticism of the compound.

Reactions seemed to range from cautious optimism to mild disappointment. Presented at last with an atom-by-atom accounting of the drug’s activity, no one felt that Vertex had been blowing smoke, but neither was anyone immediately convinced that VX-478 was all that the company had claimed. There were questions which, though easily washed away if the drug proved to be effective, now seemed to undercut Boger’s glowing predictions. Was the molecule unobtrusive enough to pass the so-called “blood-brain barrier” and enter the central nervous system, something Searle’s compound, though similar, had not been able to do? What of possible allergic reactions? VX-478 had chemical groups similar to those thought to cause some people to react violently to Bactrim, a widely used antibiotic. Though the issue of allergies in immunosuppressed, HIV-infected people seems minor, perhaps even moot, it nonetheless raised the still quite real specter of unanticipated side effects as the drug entered human trials.

Even more troubling perhaps from a business standpoint was Vertex’s patent position. Boger had delayed revealing the molecule’s structure until after the company’s European patent application was made public. But no patent on the molecule had yet been issued nor would one be for some time. Because the compound’s chemical core was tantalizingly similar to Searle’s, despite distinct differences in its overall structures, it remained possible that Vertex’s strategy for inhibiting HIV protease was, in fact, blocked. “I’m not sure their patent is as secure as they think it is,” said Dr. Carl W. Dieffenbach, chief of developmental therapeutics at the National Institute of Allergies and Infectious Diseases and the federal government’s point man for assessing new AIDS drugs.

It is a measure of Boger that he had anticipated these problems—particularly this last—and had done much to alleviate them with the Wellcome deal. As part of its due diligence, Wellcome had no doubt long ago satisfied itself that Vertex was the sole and rightful sole owner of VX-478 and its derivatives. Just as clearly, Wellcome’s patent lawyers, who had won—and kept—the rights to AZT through 10 years of intense legal strife, provided Vertex with an intimidating ally. To Boger, drug development, like war, was a strategic engagement, won or lost through attrition along multiple fronts. With little else remaining before the fall’s final “ramping” of VX-478 into patients—“There’ll still be leaves on the trees,” he predicted, though he didn’t say where—he was secure in the knowledge that Vertex was positioned to prove itself at last.

As always, he believed the future would answer for itself.