Antidote INTRODUCTION Why I Went Back Inside Vertex Twenty years ago, I wrote a book about a bold and bruising quest. It told the story of a group of entrepreneurial young scientists who left the world''s best drug company-the most admired business in America year after year-because they were confident they would be more productive on their own, starting from scratch. They aimed to design better drugs, atom by atom. Most people across the industry thought their project in a refitted construction company garage in Cambridge, Massachusetts-to build an organization that could produce dramatically improved medicines to transform the lives of people with serious diseases-was a pipe dream, a money pit, a consuming act of arrogance, an exhausting feat of hubris, a fool''s errand. "Don''t you think this is five years too early?" founding scientist and president Joshua Boger was often asked. "Yes," he would say, "but five years from now it''ll be five years too late." I found their passionate belief in science and in themselves, brimming with high purpose and combative glee, stirring and infectious as I followed them around for a couple of years while they tried to get their cash-starved company, Vertex Pharmaceuticals, off the ground. It was a rocky, exhilarating, eye-opening ride.

The chase for new leads was fierce, not just against "Mother Merck" but also top academic labs, including those led by some of their own scientific advisors, who they feared were sharing Vertex''s most prized insights with its rivals. When Boger settled for a tie in a race to publication against one of them, a Harvard professor, he told me: "I''ll take it. But I want to rub his nose in the dirt and step on his head." Such was the knife-edge between cooperation and competition in the new biopharmaceutical order. Whatever unease I felt at witnessing up close how ferocious capitalism and scientific rivalries-rather than, say, altruism-drove the search for new lifesaving drugs receded in the wake of Vertex''s precocious early success. Boger assembled a team of talented, rampantly motivated biologists, chemists, biophysicists, and computer scientists while he and his chief lieutenant tap-danced their way around the world to raise the money they would need to compete with the pharmaceutical behemoths. Though they were spectacularly outspent and outmanned in every area, he let them organize themselves, rather than try to direct them from above. He let them fail, time and again, until they came up with better approaches.

He was a visionary goal setter, an inspirer. Against all odds, within four years Vertex proved it could compete at the forefront of drug research, against the industry leaders, in several major areas at once. It had gone public and Wall Street considered it a hot stock. What I saw impressed me as a worthy, honest, compelling, even noble effort both to beat and influence the world around it-a world where life-changing new drugs were getting harder and harder to find despite the best efforts of hundreds of companies employing tens of thousands of equally gifted and passionate researchers and spending hundreds of billions of dollars on research and development. That was the story I told in The Billion-Dollar Molecule. I was encouraged by the company''s progress; pleased, too, that the book was acclaimed as an insightful look inside the world of commercial medicine. But I understood that the upstart-biotech-looks-promising version of events that I had reported wasn''t the full story, or even the main one. Boger had set out to build a drug company, but Vertex hadn''t yet produced a drug.

Nowhere near it. For him and the other company pioneers, the larger prize wasn''t organizing a research group to find better compounds; it was to build a business that could go head-to-head with the world''s most profitable drugmakers against the hardest diseases, involving some of competitive capitalism''s most complicated science and most cutthroat marketing maneuvers. I''d described the opening skirmish, not the war. The modern pharmaceutical industry emerged from one of the great triumphs of twentieth-century science. Before the 1940s, there were medicines and companies that made them, but no one had invented a method for actively finding and developing new drugs. Profits in medicine were disdained as suspect-immoral-and the companies were essentially manufacturers of fine chemical compounds. Since their products could do as much harm as good, integrity was key. Then university laboratories advanced a new approach: microbial screening.

Systematically harvesting large numbers of chemicals from "good bugs" and feeding them to "bad bugs," then monitoring and improving their activity, drugmakers produced and brought to patients the first antibacterials that had been actively sought and developed. The chase was on: for new diseases to treat, testing strategies, business opportunities, scientists, alliances with leading doctors, prestige, and money. As with all things in America, World War II was the great catalyst. Just as the companies were flexing their research and development arms to tackle other diseases, the government enlisted them in the war effort. In 1941 the Germans were rumored to have isolated the chemical secretion of the adrenal cortex, cortisone, and given it to their pilots, amping them up, emboldening them. Battlefield wounds and home-front contagions drove the need for better antibiotics, vaccines, pain relievers, and surgical products. Drugmakers were marshaled to counter the threat of a pharmacologic arms race. By midcentury, US companies had more than matched the government''s urgency, and were racing ahead, developing new biological models to screen against.

Profits began to pour in. Wall Street stood up and took notice. The companies grew spectacularly. Merck, where Boger started his career in 1979 after getting a PhD in chemistry at Harvard and doing a postdoctoral stint with future Nobel laureate Jean-Marie Lehn, was their paragon. It best represented the qualities that the industry exalted, a patient-centered, high-science focus combined with unrivaled organizational commitment to R&D. It wasn''t always the most profitable drug company-Pfizer and others were better at making money-but its research campuses in New Jersey and outside Philadelphia attracted the most promising scientists. It was where you wanted to be, the top of the pyramid. In the 1970s and 1980s, with the swift expansion of government-sponsored research spurred on by the "war on cancer," and as the universities and Wall Street simultaneously discovered a bonanza in the life sciences, there was an explosion in medical understanding, and the low-hanging fruit were quickly plucked.

Merck''s labs launched the first or second significant drugs for cholesterol, hypertension, osteoporosis, and asthma, as well as a class of pain medications known as COX-2 inhibitors. At Merck as elsewhere, scientists burned to do pathbreaking work on new medical frontiers, but increasingly, in management suites and boardrooms across the industry, the consequences of success yielded a conservative strategic consensus: move cautiously rather than struggle to produce breakthroughs; settle for modest "quick-to-market" improvements where treatments already exist, and where the resulting products can be aggressively marketed to doctors and people with chronic diseases. Gradualism held zero appeal for Boger. "Now, I don''t think there''s anything wrong with bringing an incremental advance to the marketplace; you''re not a bad person," he says. "It''s just I don''t want to do that; life''s too short." Biotechnology companies by now had joined the competition. A few top university professors or government scientists with a tantalizing idea could raise tens of millions of dollars, go out and test it, then go public-public-when all they had to sell to investors was a theory and the only certainty in their business model was years and years of progressively more unprofitable darkness. Wall Street blew hot and cold, periodically falling hard for their stories of genetic breakthroughs and miracle cures before returning to its senses.

Merck, recognizing Boger''s talents (if not buying into his ideas about building better drugs by applying advances from the biotech, software, and computer graphics industries), encouraged him to do his experiment, letting him piece together a team in immunology. But he quickly felt thwarted, impatient. Pent-up. His frustrations crystallized in the late 1980s, as many things did across the medical world, with the AIDS crisis. Drugmakers at first ignored the epidemic, seeing a small market. Off-the-shelf compounds were ineffective and toxic. When Merck entered the arena, many doctors, public health officials, and even some activists felt that the cavalry had arrived. Boger''s closest scientific friend in the company, a brilliant and brash young biologist named Irving Sigal, led Merck''s project, and Boger cleared the decks in his group to help.

CEO Roy Vagelos announced he was "damn optimistic" about Merck''s chances. In late 1988, returning from a meeting in Europe, Sigel was killed when Pan Am Flight 103, carrying 259 people and a terrorist organization''s bomb in a cargo container, exploded in a fireball over Lockerbie, Scotland. He was thirty-five. Merck scrambled to recover from its loss. Within a month, Boger was gone. So I was there when Vertex set out in its garage to overtake the "bigs." And what I saw were staggering contrasts. The major pharmaceutical companies w.