{"componentChunkName":"component---src-templates-book-page-js","path":"/molecule/14/","result":{"data":{"mdx":{"id":"6a21080c-3071-5a22-a48e-67477dd3594d","body":"function _extends() { _extends = Object.assign || function (target) { for (var i = 1; i < arguments.length; i++) { var source = arguments[i]; for (var key in source) { if (Object.prototype.hasOwnProperty.call(source, key)) { target[key] = source[key]; } } } return target; }; return _extends.apply(this, arguments); }\n\nfunction _objectWithoutProperties(source, excluded) { if (source == null) return {}; var target = _objectWithoutPropertiesLoose(source, excluded); var key, i; if (Object.getOwnPropertySymbols) { var sourceSymbolKeys = Object.getOwnPropertySymbols(source); for (i = 0; i < sourceSymbolKeys.length; i++) { key = sourceSymbolKeys[i]; if (excluded.indexOf(key) >= 0) continue; if (!Object.prototype.propertyIsEnumerable.call(source, key)) continue; target[key] = source[key]; } } return target; }\n\nfunction _objectWithoutPropertiesLoose(source, excluded) { if (source == null) return {}; var target = {}; var sourceKeys = Object.keys(source); var key, i; for (i = 0; i < sourceKeys.length; i++) { key = sourceKeys[i]; if (excluded.indexOf(key) >= 0) continue; target[key] = source[key]; } return target; }\n\n/* @jsxRuntime classic */\n\n/* @jsx mdx */\nvar _frontmatter = {\n  \"author\": \"Barry Werth\",\n  \"bookTitle\": \"The Billion-Dollar Molecule\",\n  \"isBook\": false,\n  \"numSections\": 25,\n  \"tags\": [\"a\"],\n  \"templateKey\": \"book-page\",\n  \"title\": \"Chapter Fourteen\"\n};\nvar layoutProps = {\n  _frontmatter: _frontmatter\n};\nvar MDXLayout = \"wrapper\";\nreturn function MDXContent(_ref) {\n  var components = _ref.components,\n      props = _objectWithoutProperties(_ref, [\"components\"]);\n\n  return mdx(MDXLayout, _extends({}, layoutProps, props, {\n    components: components,\n    mdxType: \"MDXLayout\"\n  }), mdx(ContentRef, {\n    id: 0,\n    mdxType: \"ContentRef\"\n  }, mdx(\"span\", {\n    className: \"stickup\"\n  }, \"O\"), \"n the road together at night, Boger and Aldrich plotted strategy. Boger typically neglected to eat breakfast or lunch, and when they got to a restaurant finally at 9 \", mdx(\"span\", {\n    className: \"smallcaps\"\n  }, \"P.M\"), \"., after a day that started at dawn with their racing to catch a plane and often ended with a third repetition of his slide show, he was famished and voluble and frequently hoarse. Chewing zinc lozenges\\u2014Boger never takes cold remedies, only metals\\u2014he and Aldrich usually ordered fish. Then they stretched out, two pinstriped tyros in soft chairs, to organize and refine their mission. \\u201CPulling money out of other people\\u2019s pockets,\\u201D Aldrich called it.\"), mdx(ContentRef, {\n    id: 1,\n    mdxType: \"ContentRef\"\n  }, \"There was an inevitability to their discourse. Vertex needed to raise enough money to run perhaps two presidential campaigns. But neither of them wanted to go back to the VCs. The preferable route\\u2014the only route, Aldrich would say, as the company began to burn more and more cash\\u2014was to raise its value to the point where other, less privileged investors could be brought in.\"), mdx(ContentRef, {\n    id: 2,\n    mdxType: \"ContentRef\"\n  }, \"This was the route he and Boger discussed. When the scientists got together they talked about science, competition, and women and what they would do when they got rich, but Boger and Aldrich talked voraciously, consummately about money: how to leverage it, what to trade for it, how to position Vertex to get more. There were deals, but deals were insufficient. The real money\\u2014the $200 million or more that Vertex would spend before it ever sold its first \", mdx(\"a\", {\n    id: \"page_254\"\n  }), \"pill\\u2014had to come from the one place such sums were available: Wall Street.\"), mdx(ContentRef, {\n    id: 3,\n    mdxType: \"ContentRef\"\n  }, \"Boger knew as much about the stock market as he did about everything else. He\\u2019d studied the development strategies of small publicly held companies, analyzed the fluctuations in their stock prices. What he hadn\\u2019t garnered on his own, he cribbed from his brother Ken, who\\u2019d taken more than a dozen such companies public. Aldrich knew more about financial instruments, but on strategic matters they were equally adept and utterly in agreement.\"), mdx(ContentRef, {\n    id: 4,\n    mdxType: \"ContentRef\"\n  }, \"\\u201CYou always want to go public when the market thinks the time is right, not when you have to,\\u201D Boger would say, Aldrich nodding in agreement.\"), mdx(ContentRef, {\n    id: 5,\n    mdxType: \"ContentRef\"\n  }, \"Scarcely was that less of a consideration than now. In the absolutely best of circumstances, Vertex was still at least five years from marketing its first drug. In January, the cost of running the labs climbed to more than $30,000 a day, only about a third of which came from Chugai. That left $20,000 to be incinerated every twenty-four hours, 365 days a year, until 1996\\u2014a minimum bonfire of $35 to $40 million. Yet that figure was misleading. It assumed, first, that the company stopped growing: a suicidal assumption, since without launching several more projects soon, Vertex was staking its future entirely on a few molecules that might be immunosuppressive in mice and an AIDS project with less than a half-dozen disgruntled scientists. It also neglected the skewed economics of drug development, where 70 percent of the overall cost arises \", mdx(\"i\", null, \"after\"), \" a drug candidate is identified. As promising as it was, Vertex was still a deep, dark hole financially, strictly for investors who could stomach such emptiness. Who else would even be interested? Who, in a regulated market, could conscionably sanction a sale to anyone else? What underwriter would see a profit in one?\"), mdx(ContentRef, {\n    id: 6,\n    mdxType: \"ContentRef\"\n  }, \"Poor as the timing for Vertex\\u2019s raising large amounts of money seemed internally, it was worse elsewhere. Wall Street\\u2019s monolithic indifference to small biomedical companies was nearly as suffocating now as it had been sixteen months earlier at the Vista. Nineteen ninety had been a miserable year, if not for biomedical stocks, for the markets in general. The Dow had its worst year in a decade. More, many big investors were in deep psychological retreat prior to the January 15, 1991, deadline for the Gulf War. Big drug firms \", mdx(\"a\", {\n    id: \"page_255\"\n  }), \"had done well, as had some of the first generation of biotech companies, which now, after more than ten years and hundreds of millions of dollars, were finally bringing a few promising drugs to market. But such success was double-edged: The young companies were widely thought to be overvalued, and even their own executives had begun cashing out. In October, for instance, Benno Schmidt sold 10,000 shares of GI, the Harvard offshoot he\\u2019d help found and served as chairman. Then, in November, J. H. Whitney, Schmidt\\u2019s venture capital company, unloaded another 41,000 shares of GI\\u201422 percent of its stake. The biggest blow came in the first week of February, when Abbott Laboratories sold its entire 6.4 percent position in Amgen, the darling of the sector. If the smart money was leaving, who but suckers remained? Wall Street surveyed the new crop of junior biomedical companies\\u2014so long from paying out, so uncertain, so confusing\\u2014and saw only what Moore and the other scientists saw: pain, grief, angst. \\u201CComing into the first part of the year,\\u201D a veteran investment banker would recall, \\u201Cwe all thought we were going to slog through another sloppy recession year. The market just seemed pathetic.\\u201D Said another: \\u201CWe were wondering how we were going to fund this industry.\\u201D\"), mdx(ContentRef, {\n    id: 7,\n    mdxType: \"ContentRef\"\n  }, \"This was Vertex\\u2019s unsparing dilemma: It was burning through capital at a startling rate, had no second project to sell, and its only option seemed to be to return to those investors who demanded the lowest valuations and exacted the highest price. Aldrich, unsurprisingly, was anxious, stern, jittery, and impatient, particularly with the scientists, who he thought were becoming lazy. It bothered him when he came in on weekends and the parking lot wasn\\u2019t full, as it had been at Biogen at a similar stage. Worse, he felt, unlike a year ago, he had nothing new to promote and the scientists weren\\u2019t giving him anything. Then, he\\u2019d said: \\u201CIn this business I\\u2019ve sometimes had to sell technology that was difficult to believe in, sometimes involving weak patent positions or marginal science. Here that\\u2019s not the case.\\u201D But he never liked AIDS as a project, even though he\\u2019d pushed Boger hard to formalize it, and saw little hope, at least in the short run, for cathepsin E. He needed to rebait his hook.\"), mdx(ContentRef, {\n    id: 8,\n    mdxType: \"ContentRef\"\n  }, \"Boger, as usual, failed to match Aldrich\\u2019s distress. \\u201CIt\\u2019s too hard,\\u201D he said equably, \\u201Cto keep looking for things that might not be there.\\u201D Science\\u2014data\\u2014would provide.\"), mdx(ContentRef, {\n    id: 9,\n    mdxType: \"ContentRef\"\n  }, mdx(\"a\", {\n    id: \"page_256\"\n  }), \"In early February, following a desultory month in the labs, the Immunophilins Project Council met to discuss publication of its work. Starzl and Fujisawa had recently announced the first international conference on FK-506 to be held in Pittsburgh at the end of August. Abstracts\\u2014brief descriptions of work to be presented\\u2014were due by the end of the month.\"), mdx(ContentRef, {\n    id: 10,\n    mdxType: \"ContentRef\"\n  }, \"Clinically, Starzl still dominated FK-506\\u2019s progress but not so totally as when only he and his surgeons had the drug. Nearly a dozen other medical centers in the United States and Europe had now begun randomized trials with discouraging results. Outside Starzl\\u2019s hands, the drug was a tempest, a demon. Contrary to his reports, FK-506, like cyclosporine, seemed to go straight for the kidneys, causing acute renal failure in up to 25 percent of all patients. The FDA, inundated with crisis calls, had to install a hot line to assuage irate transplanters, many of whom felt that Starzl, Fujisawa, and the agency had misled them dangerously. Starzl, still maintaining that FK-506 produced only low-level nephrotoxicity, believed the error was in overdosing; using Fujisawa\\u2019s protocols, the other centers were giving severalfold more of the drug than he and his group. The FDA, agreeing, was moving quietly to salvage the trials. Boger, expecting the conference might well become a brawl over safety, naturally welcomed the dispute. He\\u2019d always wanted FK-506 to succeed but never so soon or so well that it precluded the next generation of drugs.\"), mdx(ContentRef, {\n    id: 11,\n    mdxType: \"ContentRef\"\n  }, \"For Vertex, the conference was a chance to, as Boger put it, \\u201Cplant the flag.\\u201D He knew that Merck and Schreiber, still the putative leaders in basic FK-506-related research, would use the conference to showcase new work and that it was crucial for Vertex to do the same. The company needed to show some muscle. \\u201CI\\u2019d like to see ten Vertex presentations,\\u201D he said, purposely setting a higher number than any of the scientists thought possible.\"), mdx(ContentRef, {\n    id: 12,\n    mdxType: \"ContentRef\"\n  }, \"Several of them blanched. Though critical to the company, publication was also fraught with professional risk. For instance, Thomson was preparing to disclose how he and his group extracted and purified FKBP\\u2014a prospect that horrified Navia. \\u201CUntil we solve the structure,\\u201D Navia snapped, \\u201CI don\\u2019t want to tell people how we crystallized the protein. We\\u2019d be cutting our own throats.\\u201D\"), mdx(ContentRef, {\n    id: 13,\n    mdxType: \"ContentRef\"\n  }, \"Boger disagreed. To him, publication was a paradox. Scientists \", mdx(\"a\", {\n    id: \"page_257\"\n  }), \"publish to announce new work and establish authorship. Within industry, they also publish to frustrate competitors, befog imitators, and titillate investors. Boger had made aggressive patenting, the publishing arena most critical to Vertex, a hallmark of its chemistry effort\\u2014\\u201Cthrowing barrels of nails off the back of the truck,\\u201D he called it. But he thought the company risked little by promoting its other discoveries as early and prominently as possible. \\u201CAs long as we don\\u2019t put up compounds, we\\u2019re not cutting our throats,\\u201D he told Navia. \\u201CThere\\u2019s a way to do everything else.\"), mdx(ContentRef, {\n    id: 14,\n    mdxType: \"ContentRef\"\n  }, \"\\u201CThere\\u2019s two situations where you want to be aggressive about publishing. One is when you\\u2019re behind; the other is when you\\u2019re ahead. When you\\u2019re ahead, you demoralize the other guy. When you\\u2019re behind, you have nothing to lose. It\\u2019s when you don\\u2019t know that you want to be most careful.\\u201D\"), mdx(ContentRef, {\n    id: 15,\n    mdxType: \"ContentRef\"\n  }, \"Boger knew that no other issue would be more volatile among the scientists. Socially, Vertex was still as fractious as a five-year-old\\u2019s ego. As long as there had been no data to report or take credit for, it had been relatively easy to maintain a patina of unity. But now each scientist\\u2019s desire to control the disclosure of his or her work\\u2014to keep proper score\\u2014was about to come in acid conflict with Boger\\u2019s need to use Vertex\\u2019s science for his own goals. That those goals were less than purely scientific and frequently so crass as simply to lure investors set Boger irremediably apart from them. In this one area he was as much a natural enemy as Aldrich, who coldly referred to the scientists\\u2019 most exquisite insights, their noblest experiments, as \\u201Cproduct.\\u201D By rights, their science was in fact fodder. It belonged to the company, not themselves. But Boger knew he couldn\\u2019t simply expropriate it as McDonald\\u2019s does the exertions of its burger flippers. Disarming Navia, he was trying to quell an incipient mutiny before he needed to do so by stronger means.\"), mdx(ContentRef, {\n    id: 16,\n    mdxType: \"ContentRef\"\n  }, \"Throughout January and February, Boger searched Wall Street\\u2019s impenetrable geometry, looking for new angles and thinking that he recognized a powerful one in the sidelining of big institutional investors. Health portfolios, traditional high earners, were now as much as 40 percent liquid; this meant that fund managers, who make their commissions on quick growth and high turnovers, were miserably parking tens of billions of dollars in low-yield cash. \", mdx(\"a\", {\n    id: \"page_258\"\n  }), \"Those dollars, those fund managers, Boger thought, couldn\\u2019t stay out of the market long: They\\u2019d be pent up, bored, itching to get back in. Like sunstruck surfers scouring the horizon on a calm day, they\\u2019d be susceptible to the least sign of a swell.\"), mdx(ContentRef, {\n    id: 17,\n    mdxType: \"ContentRef\"\n  }, \"That needn\\u2019t be Vertex itself. Boger knew that small biomedical companies rove through the financial world in virtual lockstep. When one bolted, they all did; when one tripped, the rest collided like automatons. Certainly it had been thus in 1987, when Genentech\\u2019s disappointing sales of its much ballyhooed clot dissolver, TpA, dragged the entire biotech sector down 39 percent, plunging it into the near coma of the past three years. One or two successes among the industry\\u2019s flagships, Boger knew, would have the opposite effect, jumpstarting a free-for-all that would rain money on everyone.\"), mdx(ContentRef, {\n    id: 18,\n    mdxType: \"ContentRef\"\n  }, \"There were other interim routes. Wall Street\\u2019s cold shoulder had led three small companies recently to escape the thrall of venture capitalists without going public. The companies, not much older than Vertex, had raised more than $70 million by selling stock to qualified investors\\u2014people deemed by the Securities and Exchange Commission (SEC) to have earned more than $200,000 for at least two years or to be worth more than $1 million. So-called private placements, these sales had been at higher valuations than either venture capitalists or institutional investors were willing to pay.\"), mdx(ContentRef, {\n    id: 19,\n    mdxType: \"ContentRef\"\n  }, \"Wall Street\\u2019s gloom was fickle, Boger knew. It could turn to rapture overnight. Spastic, mercurial, spectacularly irrational, its judgments were the very opposite of the analytic, information-based, sharply realized science he was trying to accomplish in Vertex\\u2019s labs. And yet the investors were out there, reeling like the sun. Boger might disdain them, but he respected them implicitly.\"), mdx(ContentRef, {\n    id: 20,\n    mdxType: \"ContentRef\"\n  }, \"On February 22, 1991, Amgen, for the past few years a bellwether, received approval for the first of a new class of genetically engineered drugs that boost the immune system\\u2019s ability to fight infectious disease. The molecule was only the company\\u2019s second drug in eleven years, yet it couldn\\u2019t fail to arouse analysts and investors. It was being promoted for cancer patients, not to cure their cancers but to close a therapeutic loophole. Because chemotherapy and radiation kill white blood cells, the risk of secondary infections is one of the chief drawbacks to most conventional \", mdx(\"a\", {\n    id: \"page_259\"\n  }), \"treatments. Used as an adjunct, Amgen\\u2019s drug allowed doctors to push more aggressive therapies by raising the threshold of what patients could endure.\"), mdx(ContentRef, {\n    id: 21,\n    mdxType: \"ContentRef\"\n  }, \"If ever a molecule was made for Wall Street, Amgen\\u2019s GM-CSF (granulocyte macrophage colony-stimulating factor) was it. Piggybacked on the ever-growing cancer market, a short-circuit for costly hospital stays, and with a huge \\u201Coff label\\u201D potential as an all-purpose immune booster\\u2014it could have sales, some analysts predicted, of up to $750 million a year. Wall Street had run Amgen\\u2019s stock up more than 300 percent during the past twelve months in anticipation of the FDA action. Now it exploded.\"), mdx(ContentRef, {\n    id: 22,\n    mdxType: \"ContentRef\"\n  }, \"Vertex was at the far end of the continuum from Amgen, but Boger could feel the tug of universally rising expectations as Amgen\\u2019s stock price nudged $100. Wall Street bestowed great value on companies that finally made it to the finish line in the drug-approval process: Amgen\\u2019s market valuation would soon rise to more than $4.5 billion. Even as its stock overheated the following week, Boger saw in the frenzy just the jolt that Wall Street and the industry had been waiting for.\"), mdx(ContentRef, {\n    id: 23,\n    mdxType: \"ContentRef\"\n  }, \"He had little respect for Amgen\\u2019s science\\u2014\\u201CNot bad for a few cloners,\\u201D he said, echoing a remark he had made a year earlier when Genentech sold 60 percent of its stock to Swiss-owned Roche Holdings Ltd. for $2.1 billion. But the sudden lurch in momentum was unmistakable. Wall Street\\u2019s iron facade was suddenly rent with new fissures, new angles of attack. Fresh money was beginning to pour in. Boger\\u2019s calculations instantly began to reflect the change.\"), mdx(ContentRef, {\n    id: 24,\n    mdxType: \"ContentRef\"\n  }, \"\\u2022\\xA0\\xA0\\u2022\\xA0\\xA0\\u2022\"), mdx(ContentRef, {\n    id: 25,\n    mdxType: \"ContentRef\"\n  }, \"Schreiber, coveting not money but greatness, continued to publish intimidatingly. In January, he was sole author of a prestigious review article in \", mdx(\"i\", null, \"Science\"), \"\\u2014\\u201CChemistry and Biology of the Immunophilins and their Immunosuppressive Ligands [high-affinity binders],\\u201D which, as its title suggests, sought to cover the world of cyclosporine and FK-506 under a single, encompassing imprint\\u2014his. Though it contained little new data, the article laid out what had become the central focus of Schreiber\\u2019s research. He now believed that the drugs worked not by inhibiting protein folding but \", mdx(\"a\", {\n    id: \"page_260\"\n  }), \"by interfering with a far more complex process called \", mdx(\"i\", null, \"signal transduction\"), \".\"), mdx(ContentRef, {\n    id: 26,\n    mdxType: \"ContentRef\"\n  }, \"Cells, biologists know, are composed of three regions: surface, nucleus, and cytoplasm, the aqueous space in between. Much has long been known about the nucleus, which contains DNA and most of the other machinery for controlling cellular reproduction. More recently, scientists have clarified much of what occurs on the cell\\u2019s surface, where molecules \\u201Ctalk\\u201D with other molecules in their environment. For instance, with T cells, they know that when a foreign body presents itself, surface proteins identify its structure and relay the information to the nucleus. The nucleus, in return, designs antibodies that are assembled in the cytoplasm and dispatched to the surface to help repulse the intruder. This is how the body defends itself. What\\u2019s not known\\u2014and what has been of surpassing interest to molecular immunologists\\u2014is how the messages about the exact shape of the interloper and, later, the blueprints for the antibodies are transmitted protein by protein in parallel and interlocking cascades through the cytoplasm. Thus \", mdx(\"i\", null, \"signalling\"), \" or signal transduction or, as Schreiber invariably now called it, \\u201Cthe black box of signal transduction.\\u201D\"), mdx(ContentRef, {\n    id: 27,\n    mdxType: \"ContentRef\"\n  }, \"Without clearly identified actors like DNA and surface receptors, immunologists looking inside the cytoplasm had become frustrated. They could make out bits and pieces of its biochemistry but were still far from understanding its overall design. Schreiber, however, believed he possessed several vital pieces of the puzzle. To the biomedical community at large, cyclosporine and FK-506 were significant primarily as drugs. But they were perhaps even more tantalizing as submicroscopic searchlights, as probes. By latching tightly to cyclophilin and FKBP, which are found not only in T cells, but in virtually every cell in the body and in every organism, they illuminate the regions around them. For more than a year, a postdoc in Schreiber\\u2019s lab had been probing furiously with both complexes to locate their immediate partners. To Schreiber, the prize was no less than the answer to one of the most intriguing and competitive questions in biology: How do cells talk to themselves? How are they wired?\"), mdx(ContentRef, {\n    id: 28,\n    mdxType: \"ContentRef\"\n  }, \"With the \", mdx(\"i\", null, \"Science\"), \" paper, Schreiber was planting his flag over a major expanse of cell biology and moving further and further from his \", mdx(\"a\", {\n    id: \"page_261\"\n  }), \"moorings as a synthetic chemist. He was not alone in his theorizing. A relentless acquirer of information and contacts, he was picking up biology on the fly from a cadre of prominent collaborators, most ambiguously two prominent immunologists at Harvard Medical School, Steven Burakoff and Barbara Bierer, who also had connections to Vertex. Burakoff, through Schreiber, had joined Vertex\\u2019s SAB before Boger and Schreiber\\u2019s falling out and had remained on the board since; Bierer, Schreiber\\u2019s former prot\\xE9g\\xE9, was a paid consultant.\"), mdx(ContentRef, {\n    id: 29,\n    mdxType: \"ContentRef\"\n  }, \"Schreiber and Burakoff had begun collaborating on FK-506 in 1988, shortly after Schreiber\\u2019s arrival at Harvard\\u2014a productive arrangement for both. Burakoff gained access to Schreiber\\u2019s small molecules and understanding of chemistry; Schreiber, to Burakoff\\u2019s medical school connections and insights about T cells. \\u201CStuart was insatiable about biology,\\u201D Burakoff would recall. Branching out\\u2014\\u201Cdabbling,\\u201D Burakoff called it\\u2014in AIDS, they soon developed a molecule that briefly looked so promising that it was reported in more than 300 newpapers, landed Burakoff on \", mdx(\"i\", null, \"Good Morning, America\"), \", and led Harvard to spin off a new company before the compound proved to be useless.\"), mdx(ContentRef, {\n    id: 30,\n    mdxType: \"ContentRef\"\n  }, \"But the big prize for both of them remained signal transduction. \\u201CWe\\u2019re only now learning the instruments that make up the orchestra,\\u201D Burakoff would say. \\u201CWhat we haven\\u2019t been able even to approach is how the orchestration occurs and how doing all that gets coordinated to produce a symphony.\\u201D Schreiber, with his characteristic bravado and scant experience with biology, was more optimistic. \\u201CThe prospects for fundamental insights appear promising,\\u201D he concluded his paper in \", mdx(\"i\", null, \"Science\"), \".\"), mdx(ContentRef, {\n    id: 31,\n    mdxType: \"ContentRef\"\n  }, \"Others, of course, were less impressed. Responded Boger, caustically: \\u201CThere are those who would argue that firing a bazooka into the main switching box of the phone company doesn\\u2019t tell you how the phone company works.\\u201D\"), mdx(ContentRef, {\n    id: 32,\n    mdxType: \"ContentRef\"\n  }, \"In the beginning of February, Schreiber followed up his \", mdx(\"i\", null, \"Science\"), \" paper with a letter to \", mdx(\"i\", null, \"The Journal of the American Chemical Society (JACS)\"), \". His coauthors were Burakoff and Bierer. Together they suggested the existence of several other potential targets for FK-506\\u2014other FKBPs.\"), mdx(ContentRef, {\n    id: 33,\n    mdxType: \"ContentRef\"\n  }, \"Harding was distraught. The search for other binding proteins \", mdx(\"a\", {\n    id: \"page_262\"\n  }), \"had largely been his responsibility at Vertex, and now here was Schreiber, whom he\\u2019d taught to discover proteins, announcing in collaboration with Bierer and Burakoff, with whom Harding presumably ought to have been collaborating, evidence of perhaps four new immunophilins. Harding had feared that by working in industry he would forfeit his place at the forefront of research, and now it was becoming so. Worse, he felt powerless to stop it. He literally had given the company his blood and yet was no nearer the individual goals he had set for himself. He was especially pained by how it looked. \\u201CSteve and Barbara are supposed to be on our side, and we don\\u2019t know what they\\u2019re doing.\\u201D\"), mdx(ContentRef, {\n    id: 34,\n    mdxType: \"ContentRef\"\n  }, \"Boger was restrained by comparison. It was a source of intrinsic, unspoken tension between him and the scientists that while he wanted as desperately as any of them to have certain information, he cared far less, in most cases, who discovered it. Clearly, no other question was now so critical to the company as whether Harding\\u2019s and Merck\\u2019s original FKBP was the protein a Vertex drug must block in order to be immunosuppressive. However, who answered it, other than the obvious benefits to morale and for purposes of positioning the company with investors, was not nearly as important to Boger as the fact that an answer be gotten and that it quickly be made available to Vertex, preferably on favorable terms. He was annoyed that Burakoff and Bierer were still collaborating with Schreiber and that they hadn\\u2019t told him in advance of their discovery, but he was uninterested in firing any more SAB members. He was much more concerned with how to use their data.\"), mdx(ContentRef, {\n    id: 35,\n    mdxType: \"ContentRef\"\n  }, \"According to the \", mdx(\"i\", null, \"JACS\"), \" paper, there were apparently four more FK-506 binding proteins in T cells. Whereas Harding\\u2019s and Merck\\u2019s original FKBP weighed about 12,000 daltons (12,000 times as much as a hydrogen atom), Schreiber and his colleagues had found significant binding with proteins with molecular weights of about 13,000, 30,000, 60,000, and 80,000. Schreiber still believed FKBP-12, as he now called it, was the relevant target of both FK-506 and rapamycin, but the protein unquestionably had competition. A family\\u2019s worth.\"), mdx(ContentRef, {\n    id: 36,\n    mdxType: \"ContentRef\"\n  }, \"Boger suffered no public doubts, though he might have, given the implications. First, there was the obvious matter of which of the proteins was most relevant. It could be that blocking just one \", mdx(\"a\", {\n    id: \"page_263\"\n  }), \"of them was necessary for immunosuppression, or more than one, or all, or that inhibiting one was necessary but insufficient. If there was one major protein, as Schreiber assumed, what was the role of the others? It could be, too, that the side effects observed by Starzl and the other transplanters resulted from FK-506 being soaked up not by the lead target, but by the secondary ones, which\\u2014it was not yet known\\u2014might be concentrated, say, in the drug-sensitive tissues of the brain and kidneys. How did you design a drug to hit one receptor but not the others? You\\u2019d need structures for all of them. You\\u2019d need to go back to the beginning: Thomson slogging through four more protein extractions; Yamashita and Navia finding the right crystallization and heavy-atom conditions for four more proteins. Boger had adopted FK-506 as Vertex\\u2019s inaugural project, in part, because its goal appeared to be straightforward: to design a better inhibitor of a known enzyme. But this was orders of magnitude more difficult. Even if you had the five structures, it might take years to develop the biological understanding\\u2014What did each protein do? In which of the body\\u2019s cells was it found? Did the others work through still other partners, as yet unknown?\\u2014before you could even attempt to design a new molecule. \\u201CA nightmare of terror,\\u201D Murcko now called it.\"), mdx(ContentRef, {\n    id: 37,\n    mdxType: \"ContentRef\"\n  }, \"There were business horrors as well. What if Schreiber discovered the true target first and applied for the patent? Vertex might eventually have to go back to Harvard to try to license it. What if the problem simply became too complex to warrant a structure-based approach? What good were Vertex\\u2019s best molecules, its draw for investors, if there was no clear rationale for developing them? What about Chugai? Wouldn\\u2019t the discovery of another target release the company from its contract?\"), mdx(ContentRef, {\n    id: 38,\n    mdxType: \"ContentRef\"\n  }, \"These had been unspoken fears all along, and now they flailed to the surface like divers ahead of a shark. Boger moved quickly to allay the damage. As he had eighteen months earlier when the burst of sudden publicity about Starzl\\u2019s success with FK-506 threatened to preempt Vertex\\u2019s entry into immunophilins, he declared this latest development favorable to the company, a vindication of its overall approach. In fact, he told the scientists, a family of putative receptors was good news. It leveled the field. The scientific obstacles were the same now for everyone else\\u2014most notable, Merck\\u2019s \", mdx(\"a\", {\n    id: \"page_264\"\n  }), \"superior resources and head start meant even less than before. More, the essential structures of the new proteins all had to be similar to FKBP-12, otherwise FK-506 wouldn\\u2019t bind to them. Thus Vertex\\u2019s structural work wouldn\\u2019t, couldn\\u2019t, be wasted. As for business, he told them, the ultimate prize had not changed: Vertex didn\\u2019t have to produce a drug that was better than FK-506, only different. Its leads remained solid.\"), mdx(ContentRef, {\n    id: 39,\n    mdxType: \"ContentRef\"\n  }, \"Just as Boger believed in publishing early to demoralize and confound one\\u2019s competitors, it may have been that Schreiber hoped to force Vertex and the rest of the field into a costly, time-consuming reexamination and retreat, one that would help him widen his lead. But Boger wasn\\u2019t thrown off. He proposed only minor course corrections. He authorized Harding to focus his efforts on finding the actual proteins that Schreiber, Burakoff, and Bierer had postulated. Within weeks, Armistead would attach a small atomic tether to FK-506 so that Harding could set up a column similar to those he and Thomson had used earlier to fish for FKBP. Otherwise, the Schreiber \\u201Cjuggernaut,\\u201D as Moore now began to call it, failed to intimidate or dismay Boger. \\u201CIf I didn\\u2019t have compounds that work, I\\u2019d be depressed,\\u201D he said. \\u201CBut I have compounds that work. I\\u2019m elated. It makes it harder for anyone else to come in behind us.\\u201D\"), mdx(ContentRef, {\n    id: 40,\n    mdxType: \"ContentRef\"\n  }, \"After the appearance of the \", mdx(\"i\", null, \"JACS\"), \" paper, Moore called Schreiber at his lab. The two had never spoken before, but Moore wanted more information about protein conditions that Schreiber had described in his manuscript\\u2014a routine request. Schreiber, ever effusive and bearing individual Vertex scientists no particular malice, was happy to oblige. He was often like this: willing to reveal more than was inquired about, so disarmingly frank when it seemed he ought to be secretive that one wondered why. What must he be concealing? Moore mentioned that he was trying to solve the structure of FKBP by NMR. Schreiber chattily revealed that his group had assigned more than 1000 of the protein\\u2019s nearly 1600 hydrogen atoms\\u2014Moore had located fewer than 700\\u2014and left it at that.\"), mdx(ContentRef, {\n    id: 41,\n    mdxType: \"ContentRef\"\n  }, \"Moore was puzzled. Schreiber was relentless about publishing, often rushing into print with data that others thought less than earthshaking. Yet Schreiber seemed to be telling him that despite having more than enough assignments to solve the structure, his \", mdx(\"a\", {\n    id: \"page_265\"\n  }), \"group hadn\\u2019t yet \\u201Cclosed the door.\\u201D The two months since Moore had first seen the backbone of the protein had been grueling. He had buried himself in work, coming in at 9 \", mdx(\"span\", {\n    className: \"smallcaps\"\n  }, \"A.M\"), \". and often leaving after 11 \", mdx(\"span\", {\n    className: \"smallcaps\"\n  }, \"P.M\"), \"., including weekends. He\\u2019d told his wife, Lonnie, not to expect anything from him, and she hadn\\u2019t, staying up wearily to meet him with supper and a beer as he dragged in and crumpled in front of the TV. By the end of January, he had fifteen rough structures approximating the presumed actual structure, but he needed more data. Every day he expected to hear that Schreiber\\u2019s group had won, and every day, when he hadn\\u2019t, he had pushed himself on by telling himself he\\u2019d been granted another day\\u2019s reprieve. He couldn\\u2019t understand why Schreiber hadn\\u2019t simply finished him off.\"), mdx(ContentRef, {\n    id: 42,\n    mdxType: \"ContentRef\"\n  }, \"Sitting in the modeling room next to Boger\\u2019s office, Moore attacked his data with a murderous zeal. He was going as fast as he could. Within weeks, he now estimated, he would have a single consensus structure. He had become like Thomson, not as nihilistic, but locked in the isolation chamber of his own unbridled compulsion. He was oblivious to the fact that Yamashita had grown intensely jealous of him, could barely stand to be around him because he now thought Moore had won. All he wanted, saw, tasted, was the endgame of his battle with the enzyme. For the moment, nothing and no one else existed.\"), mdx(ContentRef, {\n    id: 43,\n    mdxType: \"ContentRef\"\n  }, \"\\u201CEveryone feels that they should be able to do it themselves,\\u201D he would say. \\u201CI\\u2019m just as guilty as other people in that I wanted to do this structure with as little outside intervention as possible, not because I didn\\u2019t trust other people, but because it was something I wanted to do and to prove I could do as a scientist. All during my training I always had to take my data and feed it off to someone else so that they could do the refinement or the structure determination. I said, \\u2018Fuck that.\\u2019 I hated that as a postdoc.\\u201D\"), mdx(ContentRef, {\n    id: 44,\n    mdxType: \"ContentRef\"\n  }, \"And then his computer would go down, or he\\u2019d have some trouble with software, and all his pumped-up underdog\\u2019s resolve would come hopelessly unraveled.\"), mdx(ContentRef, {\n    id: 45,\n    mdxType: \"ContentRef\"\n  }, \"\\u201CSack of shit,\\u201D he would croak, typing furiously, watching the computer devour his structures. \\u201CI have no life.\\u201D\"));\n}\n;\nMDXContent.isMDXComponent = true;","fields":{"slug":"/molecule/14/"},"frontmatter":{"isBook":false,"title":"Chapter Fourteen","bookTitle":"The Billion-Dollar Molecule","numSections":25,"tags":["a"],"author":"Barry Werth"}}},"pageContext":{"id":"6a21080c-3071-5a22-a48e-67477dd3594d"}},"staticQueryHashes":["4080856488"]}