Cushman and Ondetti set out to develop teprotide into a usable drug. The two men formed an unusual drug discovery team, since they could each seem like yin to the other’s yang. Cushman was a loquacious pharmacologist, energetic and mischievous, while Ondetti was a methodical chemist who was serious and reflective. Cushman was passionate about science but perhaps equally passionate about comic books. If you saw him at the copy machine, there was a 50 percent chance he was copying a scientific paper and a 50 percent chance he was copying a new comic book to share with the department. Despite their antithetical personalities, they were extremely effective collaborators.
They started out by seeing if they could somehow use pure teprotide as a medicine with little chemical modification. They quickly ran into a severe problem: teprotide is not orally active. The digestive enzymes in the stomach destroy the compound, which makes sense, since a pit viper’s venom is produced in the snake’s mouth and it would be catastrophic if the snake swallowed an orally active poison. If teprotide could only be administered through injections, it would be necessary to inject the drug several times a day, every day. Just thinking about this unending ordeal might release enough stress hormones to counteract any benefits from the drug!
Since neither prey nor patients enjoy injections, Cushman and Ondetti knew they needed an orally active compound if they were ever going to create a commercial version of the drug. They began synthesizing molecules that were similar to teprotide but which they hoped might withstand the rigors of the human stomach. At this stage, it is customary to evaluate thousands or even tens of thousands of molecules—this is the inevitable trial-and-error screening that all drug hunters must go through. But Cushman and Ondetti synthesized and tested only a few hundred molecules by taking a novel approach to the process of screening.
The two scientists understood the biochemistry behind the action of the ACE enzyme and thus could predict the types of compounds that would likely inhibit the enzyme. As a result, the earliest compounds they synthesized worked fairly well, and then they proceeded to further tweak these compounds based on their insights into the likely activity of different molecular structures. After each tweak, they tested the new compound to gauge its effects and evaluate the accuracy of their guesses. If drug screening is usually like randomly spinning the reels on a slot machine, then Cushman and Ondetti’s approach was more like figuring out the internal mechanics of the slot machine and then pulling the lever when the machine was about to make a payout.
Using this approach (now called “rational design”), Cushman and Ondetti rapidly synthesized a very effective ACE inhibiting compound, which they dubbed captopril. The rational design process was another landmark in the history of drug hunting. Paul Ehrlich was the first person to come up with a wholly original approach to designing a drug from scratch when he conceived of loading a toxin on a molecule of dye, though he still relied on blind trial-and-error to test a number of possible toxic warheads. In contrast, Cushman and Ondetti came up with another original approach to designing a drug from scratch, but instead of relying on blind trial-and-error, they used their knowledge of chemistry, biochemistry, and human physiology to make a series of increasingly effective educated guesses that allowed them to find what they wanted in record time and with minimal cost.
Captopril blocked the action of ACE, thereby reducing blood pressure. But it was also orally active, able to survive the corrosive acids of digestion. With their potent new drug in hand, you might think that Cushman and Ondetti were now on the glide path to drug hunting triumph. Ah, but the life of a drug hunter is never easy.
The executives at Squibb were hesitant to approve the next stage of drug development, testing the efficacy and safety of captopril, because they would require large-scale—and very expensive—clinical studies. Squibb was already selling a popular beta blocker, nadolol. The business people argued that captopril could cannibalize nadolol sales, so that any potential profits from captopril would come at the cost of reduced nadolol sales. They calculated that the net annual sales gains from captopril would be—at most—in the low hundreds of millions of dollars. Though this might seem impressively high (particularly in the 1970s), it was still not enough to justify authorizing the exorbitant expenses of clinical studies and marketing. Squibb decided to keep captopril on the shelf.
Cushman and Ondetti were very disappointed, to say the least, but since they were scientists they asked management for permission to publish their findings so that they could at least claim credit for their breakthrough research. Most pharma companies are extremely reluctant to let their scientists publish anything that might give competitors an advantage, but Cushman and Ondetti pointed out that captopril was securely patented and therefore publishing presented little risk to the company. Eventually, Squibb management consented to the drug hunters’ request—a decision probably motivated in part by feelings of sympathy for having terminated their highly original drug.
Cushman and Ondetti published the details about captopril in several leading pharmaceutical journals. Instantly, the academic medical community sat up and took notice. They recognized that the two Squibb scientists had discovered an entirely novel means for controlling blood pressure. Soon, a number of prominent doctors from major medical schools were reaching out to Squibb. These physicians assumed that Squibb would soon be starting clinical trials on the exciting new drug and they wanted to get involved and run trials at their own schools.
Such overwhelming interest from academia in a shelved drug was unprecedented, and the executives at my company huddled together and finally decided to give captropril the green light. The ensuing clinical trials demonstrated that captropril was a fantastic and safe anti-hypertensive drug. The FDA approved it in 1981. During its first full year of unrestricted commercialization, captopril generated more than a billion dollars in sales. It was so profitable, in fact, that it made more money for Squibb than the rest of its drug portfolio combined.
You might expect that landing a blockbuster drug would have sent Squibb’s stock price soaring. But for some reason that I (and my bosses) never quite understood, Squibb’s stock price was slow to reflect the soaring sales of captopril. Squibb’s competitor Bristol Myers noticed the disconnect, however, and swooped in and purchased Squibb at a discount price. Thus, in a truly ironic twist, Squibb’s demise as an independent company was caused by one of the first blockbuster drugs to be developed out of epidemiological research.
11
The Pill
Drug Hunters Striking Gold Outside of Big Pharma
The birth control pill
“No woman can call herself free who does not own and control her body. No woman can call herself free until she can choose consciously whether she will or will not be a mother.”
—Margaret Sanger, Woman and the New Race, 1922
We have ventured through the Age of Plants, the Age of Synthetic Chemistry, the Age of Dirt, and the Age of Genetic Medicine, each era marked by the opening of a new library of molecules to explore and a new generation of drug hunters rushing in to seek their Vindication. But on rare occasion, a medicine is discovered outside the major libraries, far from the well-funded labs of Big Pharma. Sometimes these stories of “independent” drug hunting cross continents and decades, involve an eclectic and strange cast of characters, wobble through mistakes, misconceptions, and misfortune, and then, at the end of it all, produce a drug that changes the history of the world. And if we wished to single out the independently developed drug that probably did more than any other to change the basic social fabric of modern civilization, it is the drug so prominent and influential that it has come to be known as “the Pill.”
The 1970s were the golden age of disaster films, when Hollywood churned out suspenseful classics like The Poseidon Adventure, Earthquake, and The Towering Inferno. These movies followed a standard formula. A wildly diverse ensemble cast separately perform individual deeds that, taken together, eventually contribute to salvation. On the bridge of the s
inking ship, the fashion model gives her designer earrings to the wounded communications officer, and he uses them to jerry-rig the damaged radio. In the bowels of the ship, the Mexican cook gives his carrot peeler to the engineer, and he uses it to repair the water pumps. In the third-class cabins, a drunken ex-boxer uses brute force to open a bulkhead and rescue trapped passengers. There’s no single narrative thread nor one single leader in charge, but their collective contributions cause them ultimately to prevail; the significance of all their individual efforts is apparent only afterward, when they are huddled together safely on shore, wet and injured but alive.
The story of the birth control pill follows the same formula.
The motley cast of characters responsible for the invention of the Pill sounds more like the cast of an Irwin Allen film than a product development team: a Swiss veterinarian, an eccentric chemist in the backwaters of Mexico, a discredited biologist, a septuagenarian feminist activist, a wealthy heiress, and a devout Catholic gynecologist. But this story commences not with a drug discovery team or a feminist campaign but with an esoteric group of professionals usually omitted from the annals of medical history—Swiss dairy farmers and their unusual method of supercharging the fertility of cows.
Dairy farms have always been big business in Switzerland. Consider the classic Swiss scene. Cows graze on high Alpine pastures with big brass bells jangling from their necks, an image as iconic as the Matterhorn. The goal of a dairy farm is to produce as much milk as possible, so dairy farmers must constantly impregnate their cows so that their udders will unceasingly produce milk. The dairy cycle is straightforward. A cow gives birth to a calf and after the calf is weaned the farmer immediately begins milking the cow’s udders. Milk production is high at first, but after some months it declines. When the cow is finally “dried off”—exhausted of milk—the cow becomes fertile again, and the farmer hurries to mate the cow to begin the cycle anew. Calving, milking, mating, calving; such is the life of a Swiss dairy farmer—and a Swiss dairy cow.
This entire process, however, relies on one crucial skill. The farmer must be able to rapidly impregnate the cow after she is dried off. The most frustrating lament heard on any Swiss dairy farm is Meine Kuh hat kein Kalb!—”My cow has no calf!” A fertile cow is a cash cow, while an infertile cow is a money pit. The farmer must keep feeding the barren beast, but no milk is produced. In the late nineteenth century, the Swiss (a people frequently caricatured for their practical and unromantic nature) experimented with ways to accelerate a sterile cow’s fertility. Eventually, one very practical and unromantic Swiss veterinarian discovered that if he inserted his hand into a cow’s anus and crushed a fragile structure in the ovary by pinching it through the wall of the rectum, the cow rapidly became fertile again.
The intrepid vet’s method soon became the “best practice” for the Swiss dairy industry, even though the farmers had no idea what exactly they were crushing. This peculiar proctological fertility technique remained unknown outside of the Swiss Alps until 1898, when a Zurich professor of veterinary medicine named Erwin Zschokke documented the procedure in a scientific journal for the first time. More importantly for the story of the Pill, Zschokke identified the precise anatomical entity that was being crushed, a yellowish ovoid structure in the ovary known as the corpus luteum.
In 1916, following up on Zschokke’s discovery, two Viennese biologists showed that an extract taken from a female rat’s corpus luteum suppressed ovulation, confirming that the structure had a role in inhibiting fertility. Later experimentation revealed that the active component of the extract was a steroid hormone called progesterone. These investigations were purely of academic interest, driven by curious scientists interested in deciphering the physiological intricacies of reproduction without any thought of the utility of their discoveries. No one imagined progesterone would have any practical use, least of all as an oral contraceptive for women. Yet Professor Zschokke’s paper set in motion an elaborate and unrecognized pharmaceutical collaboration that stretched across nations, eras, and disciplines.
Based on the corpus luteum research, it was clear that progesterone played an essential role in the female reproductive system, and biologists around the world began to study the steroid hormone. However, their curiosity was tempered by one annoying fact. There was no method within synthetic chemistry for producing progesterone in a cost-effective way. The only known procedure produced tiny quantities of the hormone at a substantial cost. Demand for progesterone among biologists eager to study its effect on animal reproductive processes far exceeded the supply, rendering the hormone prohibitively expensive for most research. During the 1920s and 30s, one of the great unsolved puzzles in chemistry was figuring out how to (cheaply) synthesize progesterone—a puzzle that attracted the attention of a most unconventional chemist.
Kurt Vonnegut’s science fiction novel Cat’s Cradle tells the story of Nobel Prize–winning physicist Felix Hoenikker. Hoenikker is motivated by a pure curiosity unsullied by politics, greed, or common sense. One day, someone asks Hoenikker what kinds of games he enjoys playing during his downtime. Hoenikker replies, “Why should I bother with made-up games when there are so many real ones?” In the novel, the government hires the fictional Hoenikker to develop the atomic bomb as part of the Manhattan Project. He begins working on the bomb but abruptly stops. When the leaders running the Manhattan Project hurry into Hoenikker’s lab to find out why, they discover the laboratory is crammed full of aquariums and turtles. Hoenikker has entirely switched his attention from the A-bomb puzzle to a tortoise puzzle: “When turtles pull in their heads, do their spines buckle or contract?”
Exasperated, the Manhattan Project leaders ask Hoenikker’s daughter what to do. She tells them not to worry. The solution is simple. Her father merely works on whatever interesting thing he finds in front of him. Just remove all the turtles, she says, and replace them with atomic bomb research. They follow her advice and sure enough, when he returns to his laboratory the next day, not finding anything more interesting to play with, he resumes his work and eventually designs the first atomic bomb. There once lived a real-life version of Felix Hoenikker, and his name was Russell Marker.
As one prominent chemist observed, “There are more stories told about Russell Marker than perhaps any chemist. They are the campfire stories that bind our profession together.” After a single year of graduate research in chemistry at the University of Maryland in 1925, Marker so impressed his advisor with his laboratory acumen that he announced Marker had accomplished enough to earn his doctoral degree. All Marker needed to do to graduate was complete a handful of courses to fulfill the university’s standard graduation requirements. But Marker refused. Stunned, his adviser warned him that if he did not take the classes and get his diploma “he would end up as a urine analyst.” Instead, the indifferent Marker dropped out of grad school. He took a research job at Ethyl Corporation, a chemical manufacturer specializing in hydrocarbons.
Ethyl was working on a problem that quickly seized Marker’s attention. When comparing the effectiveness of different automobile engine designs, how can you distinguish between the contribution of the engine and the contribution of the gasoline? The reason this was such a mystery was because there are many different types of gasoline. Gasoline is not a single molecule or even a single consistent compound, but rather a highly variable mixture of thousands of possible hydrocarbon molecules. If a particular engine was performing badly, how could you tell if it was because of a poor engine design or because you were using a crappy gasoline?
In his very first year at Ethyl, Marker solved the problem. He developed a standardized system for grading gasoline that completely avoided trying to identify the mix of molecules in the gas and instead evaluated whether the gasoline exploded when you wanted it to explode. Marker’s ingenious system compared the explosive behavior of a given batch of gasoline to a “perfect exploder” (iso-octane, which Russell assigned a rating of 100) and a “perfect non-exploder” (heptane, as
signed a rating of 0). This became the octane rating system for gasoline that we still use at the gas pump today.
Despite his quick success at Ethyl, he soon became bored with hydrocarbon chemistry and after just two years at the company he resigned. Next, he took an academic research job at the prestigious Rockefeller Institute. Over the next six years, assisted by a single lab technician, Marker published an astonishing thirty-two papers on optical chemistry—a field completely different from hydrocarbon science—several of which are still considered classics in the field. But before long he wanted to play with new chemistry games, creating friction with his boss. “Levene just wanted me to keep doing the same old research on optical rotations,” Marker explained later. “I was looking for something new.” He switched jobs once again. This time he took a position as a chemistry research fellow at Penn State University, where he immersed himself within a new puzzle—the synthesis of progesterone.
Marker knew that this was one of the great unsolved chemistry riddles of his era, and in 1936 he set about trying to devise a technique that would create the steroid hormone on an industrial scale. His approach was completely different from what anyone else was trying, and brilliant in its simplicity. Steroids are very large molecules, a fact that makes them difficult to assemble. Synthesizing a large molecule is a game of addition: chemists start out with a small molecule, then methodically attach molecule after molecule, like building with Tinkertoys, until they have assembled the full steroid. But it is fairly easy to accidentally attach an intermediate molecule in the wrong place, ruining the entire synthesis and forcing you to start all over. Generally speaking, the larger the molecule, the more difficult the synthesis. Synthesizing a small molecule (like aspirin) is usually as easy as making mac and cheese. Synthesizing a large molecule (like progesterone) is more like preparing stuffed squab chaud-froid.
The Drug Hunters Page 16