Not perhaps since cortisone, forty years earlier, had a molecule arrived promising so much. Chemists and transplanters, pathologists and cloners; specialists of the liver, kidney, skin, joints, eyes, bowels, pancreas, nervous system, and immune system; drug companies, insurance companies, ethicists; xenografters (people experimenting with replacing human organs with animal organs), oncologists, microbiologists, yeast specialists; people suffering from dozens of chronic, incurable diseases or at the precipice of death; and basic biologists, at the farthest remove from suffering, exploring the molecular essence of life—all were drawn to FK-506. They all wanted it—to examine, to take apart and reassemble, to experiment with, to treat with or be treated with—even though it remained largely untested, even though the first scientific paper documenting its effects on humans had yet to be published. In the world of modern medical research, where the rigors and jealousies of specialization act like water-tight bulkheads, compartmentalizing knowledge and separating those who pursue it from one another and from those they might benefit, and where the opportunities for hype are galactic, interest in the drug was broad, consuming, immeasurable, and in the early fall of 1989 focused irreducibly on one man, Dr. Thomas Earl Starzl.

Best known as one of the pioneers of transplant surgery, Starzl ran the world’s largest, busiest, most messianic and—at about $100 million per year in billings—most successful transplant center, the only medical center offering FK-506 to patients, at the University of Pittsburgh. Mercilessly driven, Starzl had directed the rescue and development of the drug after it was initially deemed too toxic for humans, and he hadn’t stopped there. Like a fight manager or impresario, he had also groomed the drug, choosing how it would be tested, with which patients, and under what circumstances. He had controlled what the world knew about it and when. What the spectrum of researchers and patients now clamoring for FK-506 all wanted was in fact something that only Starzl and the scores of surgeons and researchers around him had witnessed up close, a siren’s song. “A miraculous drug,” Starzl repeatedly called it. “A wonder drug. One of those drugs that comes along once in a lifetime.”

In September, Boger received an invitation to a meeting in Barcelona where the results of the first human clinical trial of FK-506—Starzl’s results—were to be presented. The session had been tacked on to a regular meeting of the European Society for Transplantation in late October, apparently in some haste, since the invitation was not formally printed, but came by fax.

It was hardly a good time for Boger to be away. Work on the labs was proceeding glacially. He still had several key positions to fill. Though much of what he was doing could be done by others, he insisted on making even the most minute decisions himself. “This is the easiest time to set things up right,” he said. “A year from now things will be twice as hard to do or impossible to fix.” And so he did everything. He designed the company’s computer network, selected the fonts for new slides, interviewed every candidate, reviewed every purchase. Working most nights until ten, he then stayed up past midnight reading scientific journals, like his father. He worked every Saturday in a den off the kitchen at home. When he left the house now to drive to Logan Airport, as he often did, his two-year-old son refused to kiss him good-bye.

Because small biomedical companies are years away from having any income, time equals money for them in a perfect sense. A company’s lifeline is computed by its “burn rate.” Six months after Vertex started writing checks, it was burning $15,000 a day. In a year the figure would double. Boger never forgot what Vertex’s burn rate was or what it demanded of him. On the day he and his family moved from New Jersey to Concord, an immaculate suburb far enough from Cambridge to be in another area code, he tripped down a flight of stairs; for the next two weeks he dragged himself around on crutches. Amy, his wife, seldom saw him anymore. They had met when she was at Radcliffe and he was tutoring in exchange for room and board at Harvard. A pediatrician, she was now taking time off to care for their two sons and was pregnant again. Resigned and supportive herself, she was having a harder time with the boys. On a night soon after the SAB meeting, Boger was in Vertex’s lunchroom at about 8 o’clock when the phone rang. It was Zachary, his five-year-old. “OK, I’m leaving,” he said. “I’m coming home right now.” Hanging up the phone, Boger shook his head admiringly: “He knows the area code.” A half hour later Boger raced out of the building, listing from a foot-high stack of journals under his arm. He flew to Barcelona the next day.

Since the goal of most researchers is publication, not lecturing, most scientific conferences are torpid rehashes of old work punctuated by tantalizing previews of forthcoming articles. Those with nothing new to say speak too much; those with real news, too little. But Starzl had published sparingly on FK-506. And so as the cavernous auditorium at the University of Barcelona began filling shortly after noon with some 500 researchers from around the world, there was a rare sense of anticipation. Starzl himself, a handsome, graying figure at sixty-three, six feet tall and thin on the verge of being gaunt, remained in the background, chewing a nicotine substitute incessantly though gritted teeth. However, there was no mistaking his role. Of the thirty-one papers to be presented, twenty-six were from his group. Only one of those had already been in print, a summary of the first sixty cases using FK-506 that had appeared in the previous week’s issue of The Lancet, a British medical journal.

Starzl’s findings were breathtaking, defying belief. FK-506 had first been given to liver transplant patients who either were rejecting their new organs on cyclosporine or couldn’t tolerate the drug’s harmful side effects—so-called rescues. Not only did most of them improve dramatically with FK-506, but many of their rejection episodes simply stopped: The patients didn’t have to be retransplanted. There was some evidence (Starzl called it “minor league”) of nephrotoxicity—kidney poisoning—but none of the hirsutism, massively swollen gums, or tremors that occasionally made transplant recipients in their teens so distraught that they quit taking cyclosporine despite being told that doing so could kill them. Overwhelmingly, patients on FK-506 felt better, recovered sooner, left the hospital quicker, and needed fewer other drugs. Their hospital bills were cut almost in half—from $244,863 with cyclosporine to $134,169 with FK-506.

One after another, the members of the Pittsburgh group built a powerful clinical case for FK-506. Yet to Boger the most tantalizing talk was that of a young Japanese surgeon, Dr. Nukio Murase, who never saw human patients. In halting English, she reported on recent animal experiments in which the entire lower viscera of rats—liver, kidneys, stomach, duodenum, pancreas, large and small bowel, everything but the spleen—were successfully transplanted using FK-506. Such experiments had been tried previously with cyclosporine, but none of the rats had survived more than thirteen days. However, Murase’s animals had lived as long as seventy-two days (some would eventually live more than seven months), with no evidence of rejection even after she had discontinued the drug. Incredibly, the surviving rats had all put on weight.

Boger marveled at the implications. If FK-506 was potent enough to keep the immune system from rejecting such a forbidding mass of tissue, it could probably be given in small enough doses to cut down substantially on side effects; therefore it would win not only the transplant market, but perhaps the autoimmunities market as well. And yet it was also inconceivable that Starzl had ordered the rat experiments simply to confirm the drug’s potency. If Starzl’s people were doing multivisceral grafts in animals, it could only be as a prelude to attempting the same operation in humans.

The session, which began at 1 P.M. and was supposed to end at 7, went on with only a single fifteen-minute break until 10:15. No one left. It was a landmark meeting, one of the very few most of them would ever attend. And yet for Starzl it was more than that. It was the apotheosis of a career that spanned practically all of modern transplantation and clinical immunology—a career of spectacular highs and profound lows played out against some of the most dramatic events in experimental medicine of the past forty years. Starzl’s heroic rescue of FK-506 had brought him to a central place in the world of scientific medicine, and it had enlarged him. And yet now, in Barcelona, he was also forced to concede, however unintentionally, the great paradox of his triumph. If FK-506 was all that Starzl said it was, it would be criminal not to give the drug to anyone who might benefit from it. Yet no drug—especially one as powerful as FK-506—is ever approved without careful comparison with those agents already available. It was lost on few people in the room, least of all those like Boger who were from the drug industry, that FK-506 might be too good a molecule in the hands of someone as daring, as unyielding, as messianic, as Tom Starzl.

“Once we started switching patients over to FK-506, we couldn’t get people to take anything else,” Starzl told the audience. “We were faced with a practical and ethical dilemma in continuing to work in a controlled manner with this drug. By summer we were experiencing a patient revolt as word spread in the hospital on the success of FK-506.”

•  •  •

Starzl has always been a figure of superhuman perseverence, determined to choose the most difficult problems and attack them with the most murderous acts of will. He was born and raised in LeMars, Iowa, a heavily Catholic county seat in the hog and corn country near the South Dakota border, where his mother was a nurse and his father owned a newspaper. Rome Starzl, a steel-eyed second-generation German-American, inherited the paper from his own father, who was tried and acquitted for sedition during World War I for editorializing against the inhumane treatment of soldiers en route to France. The stain of the episode—Rome Starzl, then attending officer’s training school in Texas, had actually been the piece’s author—never left the family, and it embodied for the young Starzl the suffocating narrowness of small-town life.

Starzl’s recollections of his father, like Boger’s, are flavored with disappointment—a man, despite hard work and a good mind, roaming through life frustrated and less than successful on his own terms. Rome Starzl ran the family paper out of obligation. His real love was science. He was an inventor whose innovations were ingenious but failed to catch on commercially and, during the late 1920s and early 1930s, a science fiction writer of certain but limited success. His first published story, “Out of the Subuniverse,” remarkably foreshadowed “The Fantastic Voyage.” It was about people who shrunk themselves to explore a microscopic cosmos—a genre that the elder Starzl would continue to pioneer until he was forced, midway through the Depression, to abandon fiction for the safer middle distance of running the Globe Post, and which his son would ultimately consider a metaphor for the life he chose and that he, young Tom, dreaded above all else.

“My father stayed in that tiny universe within a universe but never was reconciled to its limitations,” Tom Starzl would write in his memoirs. “When my time came, I wanted to escape. The fear of failing and being forced to return defeated for a lifetime of regret made trivial all other fears, even death. Like a grim watchdog, this feeling stayed until the long course was run.”

World War II catapulted Starzl out of LeMars. He joined the navy, graduating from Westminster College in Fulton, Missouri, where he’d been assigned for officer training and where, as a Latin scholar with ideas of becoming a priest, he was a gofer for Winston Churchill during his famous Iron Curtain speech in 1948. From Westminster he went to Northwestern University Medical School in Chicago. Starzl was indefatigable. In five years at Northwestern, he finished an M.D./Ph.D. in neurophysiology under the brilliant and imperious brain surgeon Dr. Loyal Davis, Nancy Reagan’s stepfather, while working almost every night at an all-night surgical clinic in one of Chicago’s worst slums. He went on to do an internship at Johns Hopkins University. Though Hopkins was widely regarded as having the best surgical program in the country, even Starzl found the school “ruthless.” Interns were on duty twenty-four hours a day, every day of the year except for one week off. The system was “pyramidal,” with students being culled after each rotation so that only one in nine made it through the entire program. Four years after he began in a class of eighteen, only Starzl and another student remained. He was thirty years old.

The fury with which Starzl left LeMars didn’t abate at Hopkins; it intensified. He ate and slept haphazardly, smoked three packs of cigarettes a day, and pushed himself beyond his physical and emotional limits. Despite his endless hours in the hospital, he had no money, as Hopkins interns were not then paid. By his own description, he was turbulent and confused. In 1955, he left Baltimore with his wife and infant son for Miami, where he worked in one of the busiest and most notorious hospitals in the world, Jackson Memorial. “Nowhere have I seen such a parade of sorrow,” he would later recall, “. . . drowned children, raped and murdered women, blond suntanned muscle builders with neat bullet holes in their heads.”

For two years Starzl operated slavishly, performing some 2000 operations—three a day. When he wasn’t operating, he worked in a primitive animal laboratory he’d set up in an empty garage across from the emergency room, experimenting on dogs that he’d gotten from the pound. In part because of the types of injuries he was seeing in Miami—gunshot wounds to the gut, massive internal bleeding due to cirrhosis—Starzl began to concentrate on the liver. Typically, his frustrations were huge. He was dissatisfied with the limits of abdominal surgery, which then was mired in academic discussions over the best techniques for arterial repair, and with physiology, which offered few new solutions for saving lives. Even more, he was dissatisfied with himself for impoverishing his family and not yet, at thirty-two, having chosen a life’s work. Pent up, he developed an ulcer. “I felt,” he would write, “like a missile looking for a trajectory.”

The next fall Starzl returned to Northwestern, having decided to stay in experimental medicine. Cancer and open-heart surgery were then the promising fields, and Starzl planned to perfect the techniques of the heart and lungs. Yet that, too, was not enough. To Starzl, thoracic surgery looked much the way LeMars had looked to his father: safe, conventional, and ultimately stultifying. “The allure of cardiac surgery had faded for me,” he wrote. “Cancer research was a possibility, but the optimistic literature of that period suggested that a cancer cure was close at hand. I thought I was too late.”

In contrast, what most appealed to Tom Starzl was the struggling field of transplantation, still dawning and considered hopeless by most experts. “The literature on transplantation of the kidney and other organs was uncompromisingly pessimistic, and therefore, paradoxically attractive,” wrote Starzl, who, it will be recalled, feared failure more than death. “This looked like the vacuum I was seeking.” As if to ensure that nothing in the path he chose for himself would be even remotely easy, Starzl decided to concentrate again on the liver, the body’s largest and most complicated glandular organ. It was 1958. The only other team seriously in the field was at Harvard, where four years earlier the first successful kidney transplant had been achieved between identical twins. Starzl could hardly have asked for a more challenging competitor. The Harvard group was directed by Dr. Francis Moore, chairman of surgery at Peter Bent Brigham Hospital, the chief clinical laboratory for the medical school. Moore, at age forty-five, was already a titan of academic medicine; the Brigham, one of the two or three best research institutions in the world. As in Miami, Starzl, yet to receive his first academic appointment, found a place to operate near Northeastern and began carving the livers out of dogs.

•  •  •

It was a sacrilege rooted in the ancient past. The earliest descriptions of animal hybrids were of the monstrous fire-breathing chimeras of Greek mythology—a lion’s head, a goat’s body, a serpent’s tail. In the shifting Middle Ages, the miracle of a leg graft by two saints, Cosmas and Damian, was a favorite subject of Renaissance painters. Though reports were sporadic, isolated attempts at transplanting whole organs began in Europe in the late nineteenth century and continued until the early 1920s. Technically primitive surgeons grafted the kidneys of sheep, pigs, goats, and lower primates into humans with abysmal results. None of the organs functioned for more than a few hours, and the patients all died within days. Nature, it appeared, abhorred the fusion of animal parts as much as the Greeks did.

Though none of the organ recipients lived long enough to reject their grafts, the search for the biological barrier to transplantation focused on the immune system. Ever since the 1870s, when Louis Pasteur first showed that invading germs provoked specific defensive chemical responses in the body, scientific immunology had been on the rise. In the 1890s, Pasteur’s work was advanced spectacularly by another chemist-turned-biologist, Paul Ehrlich. Studying how dyes bind to wool, Ehrlich ushered biology from the level to which Pasteur had brought it—the cell—to its ultimate arena: molecules. He showed that immunities were triggered by certain molecules on the surface of cells “recognizing” others. Unlike Pasteur’s work, this couldn’t be seen under a microscope. But Ehrlich’s theory that molecules bind according to specific affinities and that their interactions make up all life instantly became the touchstone for all subsequent biomedical research.

For transplanters the question was, What molecules caused the body to abhor foreign tissue and could they be disarmed? For fifty years, the problem addled immunologists. Most surgeons had long since given up. But World War II, with its “improved methods of inflicting wounds and burns,” as historian Arthur Silverstein points out, revived interest in at least one type of transplantation: skin grafting. Returning to the problem, researchers soon discovered the long-sought immunological barrier to transplantation. Molecules on the surface of a class of immune cells called T cells distinguished between substances that were native to the body and those that weren’t—between self and nonself—and initiated the production of new cells to track and kill the latter. Intriguingly, these molecules appeared to be shared genetically by some, but not all, family members.

The observations helped rationalize the first successful kidney transplant between identical twins at the Brigham in 1954—a surgical procedure that had first been devised by surgeons in Paris with organs from guillotine victims but had always ended in rejection. But the kidney was an unusual organ: There were two of them. And few people had identical twins with matching tissue types. Almost all other transplants would require taking organs from dead donors almost certainly unrelated to the recipients. Unless a way could be devised to lower the immunological threshold by suppressing the immune system, the prospects for transplanting hearts, lungs, and livers were unremittingly bleak. “On the whole,” wrote one of the fathers of modern immunology in 1961, three years after Starzl began experimenting with liver transplants in dogs, “the present outlook is highly unfavorable to success.”

This was Starzl’s “vacuum,” his “trajectory.” The physical removal and resection of the human liver, an organ about the size and shape of a boxing glove wedged inconveniently against the diaphragm, was daunting enough. It had half the body’s blood pushing through it at any given time; all its major vascular connections and ducts, tying it to the body’s largest vein as well as other organs, were buried out of sight; and it started to die almost instantly upon removal. The logistics of getting a liver out of someone who had just died and into someone else who would die without it were nightmarish, prohibitive. And yet the far larger problem, as molecular scientists had now shown, lay ahead with keeping the recipient’s immune system from destroying the graft.

As a surgeon, Starzl knew nothing about controlling the immune system, but then, hardly anyone did. Indeed, few therapies have begun more blindly than immunosuppression in the years after World War II. With the goal of simply knocking out T cells, the first transplant patients received full-body irradiation. It was like fixing a watch with a hammer; the procedure, similar to being exposed to a nuclear blast, destroyed their immunities entirely. Patients were like the “bubble boy,” who lived in a Houston hospital for twelve years before dying of massive infection within weeks of being released. Azathioprine, a powerful cell-killing anticancer drug, was also used, but it proved far too toxic over the long term. (Because the threat of rejection remains constant, transplant patients must take immunosuppressants as long as they live, lowering their tolerance for side effects, like kidney poisoning, that are cumulative.) One approach, developed later by Starzl, involved installing a shunt at the back of the neck to drain the immune system of billions of white blood cells, then pumping the patient full of antibiotics and antifungal drugs: exchanging artificial immunities for natural ones. That, too, had to be abandoned.

Starzl attempted the world’s first human liver transplant on March 1, 1963, on a three-year-old boy named Bennie Solis. By then he had performed more than 200 transplants on dogs in Chicago and in Denver, where he had moved to continue his research at the University of Colorado. On the theory of lowering doses to increase tolerance, he had come to favor a “cocktail” approach to immunosuppression—radiation, azathioprine, and cortisone—and had planned such a therapy for Bennie. It was a moot issue. The boy bled to death on the operating table.

Two months later, Starzl grafted a new liver into a forty-seven-year-old janitor who was dying of liver disease. The man lived twenty-two days—longer than two of his next three patients. Though the surgery had been a success and though the man had not rejected his graft, Starzl was scorned and rebuked. An editorial in The Annals of Internal Medicine condemned his work as “cannibalization.” Another journal accused him of “grave robbing.”

Starzl returned undeterred to the laboratory. He consumed in one year 10 percent of all the research dogs in the country. During the next two decades he would perfect many of the surgical techniques that would make the mechanics of organ transplantation more routine. He refined a bypass system that allowed blood to be diverted to the lower half of the body during surgery: His patients no longer bled to death. He developed preservative solutions that extended the time the liver could survive outside the body from four to ten hours, making it possible to ship organs by air between cities. But the defining challenge, as ever, was in immunology. The inadequacy of the available drugs resulted in a therapeutic knife edge: “Use too much and the patient doesn’t survive,” said a surgeon at the time. “Don’t use enough and the transplant doesn’t survive.” With the failure of Starzl’s shunt therapy in the late 1970s, the field appeared at a dead end. Heart transplants, which had captured the world’s imagination a decade earlier, all but stopped. By 1980, the year Starzl moved to Pittsburgh, survival rates in transplant patients were plummeting, and even Starzl had to concede that without a more specific drug the procedure was likely to die out from its own cruel ineffectiveness.

•  •  •

The Hardanger Vidda, a vast, forbidding highland plateau in Southern Norway, is nearly the size of Connecticut, yet so unrelievedly barren that the only buildings are climbers’ huts and the summer shacks of herders. There is no permanent population. Though a portion of it has been declared a national park, the Vidda (waste) is considered by most Norwegians appallingly inhospitable, a primeval terrain of lichens, mosses, and treeless grasslands dotted with glacial outfalls—enormous boulders and plunging, frigid lakes favored only by Nordic trout fishermen. In 1943, after Norwegian saboteurs destroyed a secret German heavy water plant in the nearby town of Rjukan, the brigade’s leader fled to an isolated hut in the Vidda, where he was tracked for two years before being killed by Nazis. Twenty-five years later, in the summer of 1978, a vacationing microbiologist working for the Swiss pharmaceutical company Sandoz toured the Vidda. During his stay, he routinely scooped up a spoonful of its alkaline, calcium-rich soil and placed it in a sealed petri dish to bring back for the company’s natural products screen.

There are in any fingernail of dirt between 50 million and 100 million living organisms, representing 3000 to 4000 species and living in a constant state of chemical war. To ensure their own survival, these microbial colonies develop molecules that are lethal to one another. Thus it was with the sample from the Vidda. Screeners at Sandoz discovered it contained a new molecule, which they named cyclosporine, that was fatal to a broad range of fungi. As Sandoz was screening for antifungal drugs, the compound appeared promising. But it turned out to be useless against those parasites that attack humans. For two years the drug was shelved until it was routed to an immunologist named Jean Borel, who discovered that it was also a potent immunosuppressant. Borel’s story—because immunosuppression was then considered a small, unimportant market, Sandoz repeatedly tried to kill the program, forcing Borel ultimately to test the drug on himself—quickly became famous within the drug industry, although interpretations of it vary. Screeners believe it exalts screening. Antiscreeners, like Boger, believe it shows the hair-thin luck on which screening ultimately rests, and the lunkheadedness of most big drug companies. Borel himself is more sanguine. “I’m afraid the definition of a scientist,” he has said, “is a man who can take frustration without end.”

Cyclosporine more than resuscitated the field of organ grafting. After a decade of failure, suddenly there now was a drug that not only disarmed T cells, but didn’t fatally undermine the rest of the immune system. How it worked, what the molecule bound to—those were secondary questions to be answered later in biology labs. Now, in the late 1970s, the overriding question for transplanters was toxicity. Could the drug be tolerated? The initial trials on humans revealed a terrifying medley of complications: diabetes, gout, neurotoxicity, tumors, mood swings. The worst of these from a clinical standpoint was kidney poisoning. Up to 80 percent of those taking cyclosporine eventually developed nephrotoxicity so severe that in many cases they required additional transplants.

The first human trials of cyclosporine were conducted by Sir Roy Calne of Cambridge University and were dismaying enough to dash the hopes of most transplanters. Starzl, however, had always believed that toxicity could be controlled by reducing dosage. He got the drug and immediately began administering it in a cocktail with steroids. The result was adequate immunosuppression at a therapeutic price—a wider range of diminished side effects—that most doctors and patients found tolerable. Survival rates of transplant patients suddenly soared. Transplantation units proliferated. News stories about people snatched from death with other people’s organs became nightly staples. “We’ve gone,” Starzl announced, “from the unattainable to the routine.”

Starzl had not developed cyclosporine; by the rights and rules of medicine, the credit belonged to Borel and Calne. But cyclosporine made Tom Starzl the most famous and influential transplanter in the world. Transplantation, which had been macabre and dismaying, now gleamed with optimism, and no one was more emblematic of its fearless new image. Starzl’s all-consuming determination, his stamina, his daring, his obsession—as well as his long-standing friendship with the Reagans, who helped qualify liver transplantation for reimbursement—advanced the field dramatically throughout the 1980s.

There seemed to be no limit to what Starzl could—or would—now do. In 1984, during a grueling sixteen-hour operation, he replaced both the heart and liver of a six-year-old girl, Stormie Jones, who within two weeks was skipping around the hospital. More than once he performed back-to-back liver transplants, working up to seventy-two hours at a stretch without sleep. When he did sleep, it was in a flannel-lined sleeping bag in the aisle of a chartered jet on the way to procuring organs or in blood-spattered scrubs on the floor of his office, underneath a round wooden table piled high with unfinished paperwork. Calls from all over the world, as many as a half-dozen a day, now flooded into Starzl’s office, which he began to call the “court of last resort.” With cyclosporine, Starzl and his team could now extend indefinitely the lives of people who otherwise would surely die—if only organs could be found for them, if only they could get to Pittsburgh. Shortages of organs and critical care beds, not antirejection drugs, now imposed the severest barriers on grafting, and it was against those that Starzl most frequently railed. As for cyclosporine, only the drug’s nagging toxicity—and the fact that Starzl himself hadn’t developed it—sustained his dissatisfaction.

•  •  •

In August 1986, Starzl flew to Helsinki for a meeting of the International Transplantation Society. Cyclosporine dominated the proceedings, which included a promotional side trip to the Hardanger Vidda sponsored by Sandoz. Starzl, as ever, was looking forward, not back, and was more interested in the conference. Like many others, he’d heard that a Japanese surgeon named Takio Ochiai had data on a new immunosuppressant that was one hundred times more potent than cyclosporine. Rumors of new drugs were not unusual at such meetings, and Ochiai, a middle-level professor at Chiba University, was assigned a small room to speak in. Quickly, it filled to overflowing. Borel was there. So was Calne. People attracted by the crowd pressed three- and four-deep at the doorway, straining to hear.

Ochiai’s data were tantalizing. Experimenting mainly with beagles imported from the United States, he showed that the new compound, FK-506, worked in much the same way as cyclosporine by slowing the proliferation of T cells. Like cyclosporine, the molecule had shown up in a soil screen. It had been discovered in a dirt sample taken from the lower slope of Mount Tsukuba, an hour by train from Tokyo and just a few kilometers from the central screening facility of its discoverer, Fujisawa, the third-largest drug company in Japan. (FK-506 was an abbreviation of the molecule’s identification number, FK-506009.) Like cyclosporine, FK-506 also appeared to be toxic. In dogs given less than immunosuppressive doses of the drug, Ochiai said that fully all had developed vasculitis, a weakening of the blood vessels of the heart.

After Ochiai’s talk, Borel stood up and pronounced both the presentation and the drug important new developments. Calne added that he too had the drug—although he hadn’t begun testing with it—and also considered it promising. Once again, early reports of toxic side effects were damning, but anything that appeared better than cyclosporine was considered hopeful by transplanters, who found Sandoz’s product, despite its effectiveness, unpredictable and hard to control.

Starzl, never tentative, leapt. Two weeks after returning from Helsinki, he flew to Japan to ask Fujisawa for exclusive rights to test FK-506. Starzl had never before directed the sort of basic research required for bringing a drug to clinic. Nor was his characteristic hubris suited to the impartial requirements of the job. Even if Fujisawa was looking for such a partner, the situation was complicated by a cross-licensing agreement the company had with another pharmaceutical firm, Fisons. It was through Fisons that Calne had obtained his own FK-506. Fortunately for Starzl, when Calne began testing the drug, he also found it caused vasculitis in dogs. More, Calne believed it had been fatal in some baboons. Starzl spent two weeks in Japan while Fujisawa deliberated, eventually returning home with less than a gram of FK-506—enough to begin cell assays and some experiments in rats—and a tentative commitment from Fujisawa not to give other transplanters the drug.

By the end of the year, Calne concluded that the drug was too toxic for humans and left the field. Starzl at last had what he had long desired—complete control over the testing and development of a promising new molecule. That it appeared to be poison barely intruded on Starzl’s sense of inevitability. As with himself, he was determined to make the molecule succeed.

“We were like a human machine to bring the drug through,” Dr. Mike Nalesnick, a pathologist pressed into service by Starzl to measure drug doses, would recall. “You wanted to make sure you didn’t blow it. It was your ass out there.”

Starzl had been influential at the University of Pittsburgh Medical Center before; he was its star, its first international figure since Jonas Salk, and Pitt was rising in prominence because of him. Now his demands and the reaction to them among those who were less favored multiplied furiously. Insisting on independence, he refused all financial support from Fujisawa—a decision that eventually would cost the university up to $8 million a year. Even before the Helsinki meeting, Starzl and a small group had began meeting Monday nights to discuss new immunosuppressive therapies. Now the group burgeoned to nearly one hundred—surgeons, oncologists, organ specialists, animal toxicologists, pharmacologists, technicians. Where Starzl couldn’t find an expert, he willed one, as he did with Nalesnick, by importing someone from another field or, as with an Italian pancreatic specialist, Dr. Camillo Ricordi, simply ordering the defenseless man to leave Milan for Pittsburgh. He commandeered labs, operating rooms, scarce intensive care beds. Characteristically, he stopped at nothing.

During the next twenty-nine months, Starzl’s team performed hundreds of studies on mice, rats, pigs, baboons, and dogs, eventually showing that Calne’s dog studies were at least ambiguous and should not stop the drug’s progress. (“Drugs kill dogs,” says Boger about the animal’s well-known proclivity for showing side effects unobserved in other species, “and dogs kill drugs.”) Working closely with the FDA, which sanctions all such clinical trials in the United States, Starzl’s team produced compelling enough evidence to warrant testing the drug in people. Calne and others still claimed FK-506 was too toxic for humans. Criticism of Starzl’s ad hoc research methods and army of medical conscripts was considerable. But by now, Starzl was absolutely convinced that the FK-506 was the best immunosuppressive therapy ever developed.

“In every animal model, in every organ, FK-506 won,” he said. “It wasn’t bold to give the drug to people. It was the most responsible thing we could have done.”

•  •  •

As a first candidate for a powerful medication of unknown risks and benefits, Robin Ford was a natural choice. Twenty-eight years old, she was dying. Her third liver graft in three years was failing, she had lost a kidney, and her remaining one was so damaged by cyclosporine that it, too, was shutting down. On February 28, 1989—less than a month after Boger chose immunophilins as Vertex’s inaugural project—doctors prepared Ford to receive cyclosporine and FK-506 together in a last-ditch attempt to save her life.

Starzl aside, concern over the new drug remained such that Ford was required to sign a release detailing those side effects most prevalent in animals—vomiting, weight loss, elevation of blood sugar—that read: “Other side effects, including death, are possible in humans, but cannot be anticipated.” As in the first stage of all clinical testing of new drugs, the initial goal was to establish that FK-506 was not prohibitively toxic. Officially, at least, Ford was not expected to improve on the drug, only to show whether it could be endured. A full complement of emergency equipment, including a resuscitator, was wheeled into her room.

Ford spent much of the first day under critical observation. Starzl flew to Paris to attend an emergency meeting to discuss the feasibility of trans-Atlantic organ sharing. Those left to supervise Ford’s treatment—three surgeons, John Fung, Ashok Jain, and Saturo Todo, and a pharmacologist, Raman Venkataramanan—were “very anxious,” Jain recalls. “We didn’t know the optimum dose. We didn’t know how to treat her.”

On the third day of taking both drugs, Ford began vomiting. She complained of a severe headache and nausea. “I said, ‘Oh God, maybe the drug really is no good,’ ” Jain recalls. Distraught, he and others began to argue in favor of stopping the FK-506, though Ford herself wanted to stay on it. According to Starzl, his staff came within “a hair” of pulling her off FK-506—a decision that not only would have caused her to reject her new liver but almost certainly would have killed the drug’s progress outright—before he, returning from Paris, examined her. Starzl believed Ford was reacting to the two powerful immunosuppressants in her system. Since she couldn’t tolerate cyclosporine, he reasoned, she had nothing to lose by coming off the drug. Consulting with the FDA, Starzl decided to take Ford off cyclosporine to see if she could survive on FK-506 alone.

Forty-eight hours later, Ford’s nausea dissipated. She was able to hold food. Within two weeks, biopsies showed, her immune system stopped rejecting her new liver. More startling, her liver function began to improve: From this one case, FK-506 seemed actually to revive dying tissue. “It was like a miracle, like a dream,” Jain says. Because severe kidney damage, unlike serious liver damage, is irreversible, Ford eventually required another kidney transplant, but with the FK-506, she tolerated that, too. After about a month she was home, returning eventually to work and a normal life.

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As Boger would guess in Barcelona, Starzl’s attachment to FK-506 went deeper than wanting to advance the cause of liver transplantation—a cause he’d more or less helped bring to its climactic stage with cyclosporine. Starzl was more relentless than that, his goals hungrier, more personal. The testing of FK-506 in humans was necessarily secretive—no drug developer wants to prejudice the FDA, or inflame the public prematurely—but Tom Starzl was not a reclusive man.

As at many other times in his life, Starzl in the first half of 1989 was embroiled publicly on several fronts at once. Six weeks before giving FK-506 to Robin Ford—Boger had sensed correctly here, too—Starzl was forced to halt a new series of multiorgan transplants at Pittsburgh. Two three-year-old girls who had each received five new organs—stomach, liver, pancreas, and large and small bowel—had died the previous year. Though Starzl blamed cyclosporine, the deaths invited yet another round of public questioning of his methods. “I believe,” Harvard’s Francis Moore, Starzl’s primary competitor in the early days of liver transplantation, wrote in a leading medical journal, “that this procedure shouldn’t be performed again until it has been shown . . . that there is a palpable likelihood of success.”

Meanwhile, Starzl had begun to talk openly at the medical center and, in a few cases, publicly about FK-506. By the time the next rescue patient was given the drug—a thirty-eight-year-old New Orleans contractor named Lester Wilson, who’d previously received five new livers—Starzl was so convinced of its superiority that he no longer considered it ethical to prescribe cyclosporine. The position inflamed the University of Pittsburgh Medical Center’s Institutional Review Board (IRB), which was responsible for protecting patients—and the hospitals themselves—from overzealous experimenters and overstated claims. “Starzl says, ‘Trust me, I’m the expert,’ ” complained Dr. Richard Cohen, head of the thirty-member IRB. “We’ve had to protect him from himself.”

That anyone should think that Starzl would need such protection only drove him to more militant extremes. He responded by attacking in the darkest, most unyielding terms those who insisted that he compare the two drugs blindly in clinical trials, even though, as he knew, the FDA would eventually insist on such comparison testing. “In this cruel world there have been too many examples of people who’ve conducted unconscionable experiments on human subjects because they said their superiors ordered them to,” Starzl said in a speech at the medical school. “The worst of them ended up in the dock at Nuremburg. I don’t want to be put in that position.”

Starzl received a temporary reprieve from his travails in April, when the U.S. Justice Department, after years of investigation, decided not to prosecute him for violating the National Organ Transplant Act—an act he helped foster. A Pulitzer Prize-winning series in the Pittsburgh Press had shown that in the mid-1980s Starzl’s unit transplanted a disproportionate number of foreign nationals, who paid higher rates and were not often as ill or hadn’t waited as long as other patients. Normally skillful with the media, Starzl had dug himself deeper by telling a reporter that the organs reserved for foreigners were “crumbs” and “bottom of the barrel.” Eventually published, the remarks had been impossible to wash away, Pittsburgh and the world being, in that respect, no larger or more forgiving than LeMars.

Assailed in the press, entangled with the medical center review board, barred by the lack of a more potent immunosuppressant from developing new transplant operations, stung by peer criticism, Starzl was explosive. A notorious taskmaster, he began to drive his people even harder in anticipation of the meeting in Barcelona, where the world would see their work and where he expected they would be vindicated.

In September, Starzl flew to Minneapolis to give a talk on “cluster” transplants. These involved removing the liver, stomach, spleen, duodenum, pancreas, and large and small bowels and replacing them just with a liver infused with pancreatic islet cells. Another of Starzl’s experiments, the procedure made it possible for transplant recipients who’d had their pancreases removed to live without depending on daily insulin shots. Animal studies with FK-506 had shown surprising success with the procedure, which Starzl now suggested might be used to cure people whose abdomens were ravaged by metastatic cancer. The talk was vintage Starzl—low-key and dignified and startlingly heretical. Transplanting for Starzl had always been a straightforward therapeutic trade-off: remove and replace the sick parts of an otherwise healthy person to save the whole. The more potent the immunosuppression, the more parts that could be removed. After the conference, Starzl was approached by Lawrence Altman, a reporter from the New York Times, who said he’d like to visit Pittsburgh and write about the cluster procedure.

For credibility’s sake as well as for the planting of a firm flag scientifically, Starzl did not want his clinical work in FK-506 announced publicly before it appeared in The Lancet. But from the moment Altman arrived in Pittsburgh, it was clear something more was happening than animal studies. Whether or not it was the “patient revolt” Starzl would describe in Barcelona, Altman, a physician, couldn’t help but inquire. He wasn’t alone. A reporter from the Pittsburgh Post-Gazette, Henry Pierce, also had begun hearing about Starzl’s new miracle drug and was preparing to write about it.

Starzl tried to delay the newspapers from publishing until the conference in Barcelona, but without a guaranteed exclusive, neither paper was willing to wait. Then, in mid-October, Starzl heard from Pierce that the Post-Gazette’s editors feared being scooped and were planning to print his story. He immediately called Altman, thereby crafting the release date—October 18, 1989—himself. It was the day of the San Franciso earthquake, but the stories, ready in time for the early editions, both made the top of the front page. In the case of the Times, the placement guaranteed wide distribution by the news services, the television networks, and Cable News Network (CNN). By the end of the day, calls began flooding into Pittsburgh from around the world—journalists, doctors, patients, drug industry analysts—all wanting breathlessly to know more about Tom Starzl’s miraculous new drug.

•  •  •

At Vertex, several hearts sank at the news. Scientists don’t rely on the Times, or any newspaper, for scientific information. But to see the Times give the story rare above-the-fold coverage—headlined “Great Success with Drug in Transplants of Organs,” the piece ran sixty column inches, more than the paper devotes to the election of most European heads of state—was unnerving, especially as it touted the drug’s safety. “FK-506 has shown little evidence of toxicity in humans so far,” Altman wrote. It wasn’t long before chemist David Armistead, speaking by informal proxy for several others, wondered aloud at a rump meeting of the Vertex scientific staff: “What if this is the wonder drug of the century? Why should we go after it?”

Boger, who is bemused in general by the symbiosis of the medical community and the press and in particular by “breakthroughs” that are announced to the public before other scientists have reviewed them, was not in serious danger of being second-guessed because of FK-506’s sudden publicity. The drug still had a long way to go, and everyone agreed that Vertex’s rationale for chasing it remained sound. But some members of the board of directors already had called anxiously that morning, and how Boger responded was the first real test of his leadership. It was not too late to launch another program. With any drug project, it was always better to cut one’s losses early. Characteristically, Boger was staunch and unequivocal.

“This is good news for us,” he told the staff. “It raises the stakes. It shows that cyclosporine is a beatable compound, and it heats up the area. This whole way of going after autoimmune diseases looks more reasonable because of [FK-506’s] reduced toxicity.” Indeed, his first comment after reading the Times piece had been: “I’d be happy if by the time we have a compound to go into clinical trials, FK is doing $3 billion in sales. I want Fujisawa to succeed.”

As with so much else about Boger, the iconoclasm at first seemed brash. But as the others began to hear him analyze the situation, they quickly came to see that he was right. FK-506 was probably going to be a blockbuster drug: It would steal the transplant market from cyclosporine and would probably be safe enough to open up the autoimmune market. But, the Times article notwithstanding, it was unlikely to be safe enough to capture that market as well, so the greatest prize would be left for the next generation of compounds. Vertex couldn’t have asked for a better scenario.

Of course, every major pharmaceutical company in the world would soon come to the same conclusions and rush ahead with programs in immunosuppression, clogging the field. But that burst of attention was likely to be less than it seemed. Most of them had already spent the better part of a decade screening for new molecules to replace cyclosporine, with only a single contender emerging—FK-506. Hundreds of chemists at Sandoz and elsewhere had tried for years to redesign cyclosporine to make it safer without a single clinical candidate to show for their efforts. Without their own leads, many of the companies would now likely end up looking to underwrite a small specialized research partner, which played directly into Vertex’s strategy. Either way, it appeared, Vertex won.

There were only two problems. The first was Merck, which already had a sizable program in the area. Merck had set the industry standard with its billion-dollar hypertension drug, Vasotec, for capturing a growing market with a second-generation compound. Confronted in the mid-1980s with Squibb’s development of Capoten, a drug based on a molecule found initially in pit viper venom, Merck had put scores of chemists on the task of improving it, then followed up with a withering sales campaign so effective that it ended up beating Squibb in the market even though Capoten was launched first and was much the same drug. Huge resources could be brought to bear if Merck suddenly got more serious.

Which led to the second concern: Vertex’s unfinished labs. As Merck’s most spectacular defection in years, Boger knew as well as anyone the limits of its science. As he told Knowles at the SAB meeting, he thought Vertex could defeat Merck going head-to-head. But that presumed an equal start. Merck, which had the greatest research capacity of any drug company in the world, had been working on improving FK-506 for more than a year under a program set up largely by Boger himself. Vertex, meanwhile, had fifteen scientists sitting on their hands. On the day the Times piece came out, they began the morning bristling with competitiveness, but with no place to put their fire, they were soon back at their rented steel desks, rechecking their equipment orders and wondering when they would start. For all but Boger, it was another slow day.