Part of this expansion reflected the birth of a brand new industry: biotechnology. After 1975, DNA was no longer solely the concern of biologists trying to understand the molecular underpinnings of life. The molecule moved beyond the academic cloisters inhabited by white-coated scientists into a very different world populated largely by men in silk ties and sharp suits. The name Francis Crick had given his home in Cambridge, the Golden Helix, now had a whole new meaning.
CHAPTER FIVE
DNA, DOLLARS, AND DRUGS:
BIOTECHNOLOGY
Herb Boyer has a way with meetings. We have seen how his 1972 chat with Stanley Cohen in a Waikiki deli led to the experiments that made recombinant DNA a reality. In 1976, lightning struck a second time: the scene was San Francisco, the meeting was with a venture capitalist named Bob Swanson, and the result was a whole new industry that would come to be called biotechnology.
Only twenty-seven when he took the initiative and contacted Boyer, Swanson was already making a name for himself in high-stakes finance. He was looking for a new business opportunity, and with his background in science he sensed one in the newly minted technology of recombinant DNA. Trouble was, everyone Swanson spoke to told him that he was jumping the gun. Even Stanley Cohen suggested that commercial applications were at least several years away. As for Boyer himself, he disliked distractions, especially when they involved men in suits, who always look out of place in the jeans-and-T-shirt world of academic science. Somehow, though, Swanson cajoled him into sparing ten minutes of his time one Friday afternoon.
Ten minutes turned into several hours, and then several beers when the meeting was adjourned to nearby Churchill's Bar, where Swanson discovered he had succeeded in rousing a latent entrepreneur. It was in Derry Borough High School's 1954 yearbook that class president Boyer had first declared his ambition "to become a successful businessman."
The basic proposition was extraordinarily simple: find a way to use the Cohen-Boyer technology to produce proteins that are marketable. A gene for a "useful" protein – say, one with therapeutic value, such as human insulin – could be inserted into a bacterium, which in turn would start manufacturing the protein. Then it would just be a matter of scaling up production, from petri dishes in the laboratory to vast industrial-size vats, and harvesting the protein as it was produced. Simple in principle, but not so simple in practice. Nevertheless, Boyer and Swanson were optimistic: each plunked down $500 to form a partnership dedicated to exploiting the new technology. In April 1976 they formed the world's first biotech company. Swanson's suggestion that they call the firm "Her-Bob," a combination of their first names, was mercifully rejected by Boyer, who offered instead "Genentech," short for "genetic engineering technology."
Insulin was an obvious commercial first target for Genentech. Diabetics require regular injections of this protein since their bodies naturally produce either too little of it (Type II diabetes) or none at all (Type I). Before the discovery in 1921 of insulin's role in regulating blood-sugar levels, Type I diabetes was lethal. Since then, the production of insulin for use by diabetics has become a major industry. Because blood-sugar levels are regulated much the same way in all mammals, it is possible to use insulin from domestic animals, mainly pigs and cows. Pig and cow insulins differ slightly from the human version: pig insulin by 1 amino acid in the 51-amino-acid protein chain, and cow insulin by 3. These differences can occasionally cause adverse effects in patients; diabetics sometimes develop allergies to the "foreign" protein. The biotech way around these allergy problems would be to provide diabetics with the real McCoy, human insulin.
With an estimated 8 million diabetics in the United States, insulin promised a biotech gold mine. Boyer and Swanson, however, were not alone in recognizing its potential. A group of Boyer's colleagues at the University of California, San Francisco (UCSF), as well as Wally Gilbert at Harvard, had also realized that cloning human insulin would prove both scientifically and commercially valuable. In May 1978, the stakes were raised when Gilbert and several others from the United States and Europe formed their own company, Biogen. The contrasting origins of Biogen and Genentech show just how fast things were moving: Genentech was envisioned by a twenty-seven-year-old willing to work the phones; Biogen was put together by a consortium of seasoned venture capitalists who head-hunted top scientists. Genentech was born in a San Francisco bar, Biogen in a fancy European hotel. Both companies, however, shared the same vision, and insulin was part of it. The race was on.
Inducing a bacterium to produce a human protein is tricky. Particularly awkward is the presence of introns, those noncoding segments of DNA found in human genes. Since bacteria have no introns, they have no means for dealing with them. While the human cell carefully "edits" the messenger RNA to remove these noncoding segments, bacteria, with no such capacity, cannot produce a protein from a human gene. And so, if E. coli were really going to be harnessed to produce human proteins from human genes, the intron obstacle needed to be overcome first.
The rival start-ups approached the problem in different ways. Genentech's strategy was to chemically synthesize the intron-free portions of the gene, which could then be inserted into a plasmid. They would in effect be cloning an artificial copy of the original gene. Nowadays, this cumbersome method is seldom used, but at the time Genentech's was a smart strategy. The Asilomar biohazard meeting had occurred only a short time earlier, and genetic cloning, particularly when it involved human genes, was still viewed with great suspicion and fell under heavy regulation. However, by using an artificial copy of the gene, rather than one actually extracted from a human being, Genentech had found a loophole. The company's insulin hunt could proceed unimpeded by the new rules.
Genentech's competitors followed an alternative approach – the one generally used today – but, working with DNA taken from actual human cells, they would soon find themselves stumbling into a regulatory nightmare. Their method employed one of molecular biology's most surprising discoveries to date: that the central dogma governing the flow of genetic information – the rule that DNA begets RNA, which in turn begets protein – could occasionally be violated. In the 1950s scientists had discovered a group of viruses that contain RNA but lack DNA. HIV, the virus that causes AIDS, is a member of this group. Subsequent research showed that these viruses could nevertheless convert their RNA into DNA after inserting it into a host cell. These viruses thus defy the central dogma with their backward RNA → DNA path. The critical trick is performed by an enzyme, reverse transcriptase, that converts RNA to DNA. Its discovery in 1970 earned Howard Temin and David Baltimore the 1975 Nobel Prize in Physiology or Medicine.
Reverse transcriptase suggested to Biogen and others an elegant way to create their own intron-free human insulin gene for insertion in bacteria. The first step was to isolate the messenger RNA produced by the insulin gene. Because of the editing process, the messenger RNA lacks the introns in the DNA from which it is copied. The RNA itself is not especially useful because RNA, unlike DNA, is a delicate molecule liable to degrade rapidly; also the Cohen-Boyer system calls for inserting DNA – not RNA – into bacterial cells. The goal, therefore, was to make DNA from the edited messenger RNA molecule using reverse transcriptase. The result would be a piece of DNA without the introns but with all the information that bacteria would require to make the human insulin protein – a cleaned-up insulin gene.
In the end Genentech would win the race, but just barely. Using the reverse transcriptase method, Gilbert's team had succeeded in cloning the rat gene for insulin and then coaxing a bacterium into producing the rat protein. All that remained was to repeat the process with the human gene. Here, however, is where Biogen met its regulatory Waterloo. To clone human DNA, Gilbert's team had to find a P4 containment facility – one with the highest level of containment, the sort required for work on such unpleasant beasts as the Ebola virus. They managed to persuade the British military to grant them access to Porton Down, a biological warfare laboratory in the south of England.
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In his book about the race to clone insulin, Stephen Hall records the almost surreal indignities suffered by Gilbert and his colleagues.
Merely entering the P4 lab was an ordeal. After removing all clothing, each researcher donned government-issue white boxer shorts, black rubber boots, blue pajama-like garments, a tan hospital-style gown open in the back, two pairs of gloves, and a blue plastic hat resembling a shower cap. Everything then passed through a quick formaldehyde wash. Everything. All the gear, all the bottles, all the glassware, all the equipment. All the scientific recipes, written down on paper, had to pass through the wash; so the researchers slipped the instructions, one sheet at a time, inside plastic Ziploc bags, hoping that formaldehyde would not leak in and turn the paper into a brown, crinkly, parchment-like mess. Any document exposed to lab air would ultimately have to be destroyed, so the Harvard group could not even bring in their lab notebooks to make entries. After stepping through a basin of formaldehyde, the workers descended a short flight of steps into the P4 lab itself. The same hygienic rigmarole, including a shower, had to be repeated whenever anyone left the lab.
All this for the simple privilege of cloning a piece of human DNA. Today, in our less paranoid and better informed times, the same procedure is often performed in rudimentary labs by undergraduates taking introductory molecular biology. The whole episode was a bust for Gilbert and his team as they failed to clone the insulin gene. Not surprisingly they blamed their P4 nightmare (see Plate 30).
The Genentech team faced no such regulatory hurdles, but their technical challenges in inducing E. coli to produce insulin from their chemically synthesized gene were considerable all the same. For Swanson the businessman, the problems were not merely scientific. Since 1923, the U.S. insulin market had been dominated by a single producer, Eli Lilly, which by the late seventies was a $3 billion company with an 85 percent share of the insulin market. Swanson knew Genentech was in no position to compete with the 800-pound gorilla, even with a genetically engineered human insulin, a product patently superior to Lilly's farm-animal version. He decided to cut a deal and approached Lilly, offering an exclusive license to Genentech's insulin. And so as his scientist partners beavered away in the lab, Swanson hustled away in the boardroom. Lilly, he was sure, would agree; even such a giant could ill afford to miss out on what recombinant DNA technology represented, namely the very future of pharmaceutical production.
But Swanson wasn't the only one with a proposal, and Lilly was actually funding one of the competing efforts. A Lilly official had even been dispatched to Strasbourg, France, to oversee a promising attempt to clone the insulin gene using methods similar to Gilbert's. However, when the news came through that Genentech had gotten there first, Lilly's attention was instantly diverted to California. Genentech and Lilly signed an agreement on August 25,1978, one day after the final experimental confirmation. The biotech business was no longer just a dream. Genentech would go public in September 1980. Within minutes its shares rose from a starting price of $35 to $89. At the time, this was the most rapid escalation in value in the history of Wall Street. Boyer and Swanson suddenly found themselves worth some $66 million apiece.
Traditionally in academic biology, all that mattered was precedence: who made the discovery first. One was rewarded in kudos, not cash. There were exceptions – the Nobel Prize, for instance, does come with a hefty financial award – but in general we did biology because we loved it. Our meager academic salaries certainly did not offer much of an inducement.
With the advent of biotechnology, all that changed. The 1980s would see changes in the relationship of science and commerce that were unimaginable a decade before. Biology was now a big-money game, and with the money came a whole new mind-set, and new complications (see Plate 33).
For one thing, the founders of biotech companies were typically university professors, and not surprisingly the research underpinning their companies' commercial prospects typically originated in their university labs. It was in his Zurich University lab, for instance, that Charles Weissmann, one of Biogen's founders, cloned human interferon, which, as a treatment for multiple sclerosis, has since become the company's biggest moneymaker. And Harvard University hosted Wally Gilbert's ultimately unsuccessful attempt to add recombinant insulin to Biogen's roster of products. Certain questions were soon bound to be asked: Should professors be permitted to enrich themselves on the basis of work done in their university's facilities? Would the commercialization of academic science create irreconcilable conflicts of interest? And the prospect of a new era of industrial-scale molecular biology fanned the still-glowing embers of the safety debate: with big money at stake, just how far would the captains of this new industry push the safety envelope?
Harvard's initial response was to form a biotech company of its own. With plenty of venture capital and the intellectual capital of two of the university's star molecular biologists, Mark Ptashne and Tom Maniatis, the business plan seemed a sure thing; a major player was about to enter the biotech game. In the fall of 1980, however, the plan fell apart. When the measure was put to a vote, the faculty refused to allow Fair Harvard to dip its lily-white academic toes into the murky waters of commerce. There were concerns that the enterprise would create conflicts of interest within the biology department: with a profit center in place, would faculty continue to be hired strictly on the basis of academic merit or would their potential to contribute to the firm now come into consideration? Ultimately, Harvard was forced to withdraw, giving up its 20 percent stake in the company. Sixteen years later, the cost of that call would become apparent when the firm was sold to the pharmaceutical giant Wyeth for $1.25 billion. And to this day, Harvard's Department of Molecular and Cellular Biology lacks a designated endowment to support research above the cost of salaries.
The decision of Ptashne and Maniatis to press on regardless precipitated a fresh set of obstacles. Mayor Vellucci's moratorium on recombinant DNA research in Cambridge was a thing of the past, but anti-DNA sentiment lingered on. Carefully avoiding a flashy high-tech name like Genentech or Biogen, Ptashne and Maniatis named their company Genetics Institute, hoping to evoke the less threatening fruit fly cra of biology, rather than the brave new world of DNA. In the same spirit, the fledgling company decided to hang its shingle not in Cambridge but in the neighboring city of Somerville. A stormy hearing in Somerville City Hall, however, demonstrated that the Vellucci effect extended beyond the Cambridge city limits: Genetics Institute was denied a license to operate. Fortunately the city of Boston, just across the Charles River from Cambridge, proved more receptive, and the new firm set up shop in an empty hospital building in Boston's Mission Hill district. As it became more and more apparent that recombinant methods posed no health or environmental risk, the Vellucci brand of antibiotech fanaticism could not endure. Within a few years, Genetics Institute would move to North Cambridge, just down the road from the university parent that had abandoned it at birth.
Over the past twenty years, the suspicion and sanctimoniousness attending the early days of the relationship between academic and commercial molecular biology has given way to something approaching a productive symbiosis. For their part universities now actively encourage their faculty to cultivate commercial interests. Learning from Harvard's mistake with Genetics Institute, they have developed ways to cash in on the lucrative applications of technology invented on campus. New codes of practice aim to prevent conflicts of interest for professors straddling both worlds. In the early days of biotech, academic scientists were all too often accused of "selling out" when they became involved with a company. Now involvement in commercial biotech is a standard part of a hotshot DNA career. The money is handy, and there are intellectual rewards as well because, for good business reasons, biotech is invariably on the scientific cutting edge.
Stanley Cohen proved himself a forerunner not only in technology but also in the evolution from a purely academic mind-set to one adapted to the age of big-bucks biology. He had known from the b
eginning that recombinant DNA had potential for commercial applications, but it had never occurred to him that the Cohen-Boyer cloning method should be patented. It was Niels Reimers in Stanford's technology licensing office who suggested that a patent might be in order when he read on the front page of the New York Times about the home team's big win. At first Cohen was dubious; the breakthrough in question, he argued, was dependent on generations of earlier research that had been freely shared, and so it seemed inappropriate to patent what was merely the latest development. But every invention builds on ones that have come before (the steam locomotive could only come after the steam engine); and patents rightly belong to those innovators who extend the achievements of the past in decisive and influential ways. In 1980, six years after Stanford first submitted the application, the Cohen-Boyer process was granted its patent.
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