Penny le Couteur & Jay Burreson

by Napoleon's Buttons: How 17 Molecules Changed History

  Sarsasapogenin, the sapogenin from the sarsaparilla plant

  Marker was sure it could be done, and he was right. The process he developed produced the basic four-ring steroid system that, with only a few more steps, gave pure synthetic progesterone, chemically identical to that produced in the female body. And once the side group was removed, synthesis of many other steroidal compounds became possible. This procedure—the removal of the sapogenin side grouping from the steroid system—is still used today in the multibillion-dollar synthetic hormone industry. It is known as the “Marker degradation.”

  Marker’s next challenge was to find a plant that contained more of the starting material than sarsaparilla. Steroid sapogenins, derived by removing sugar units from the parent saponins, can be found in numerous plants other than the sarsaparillas, including trillium, yucca, foxglove, agave cactus, and asparagus. His search, involving hundreds of tropical and subtropical plants, eventually led to a species of Dioscorea, a wild yam found in the mountains of the Mexican province of Veracruz. By now it was early 1942, and the United States was involved in World War II. Mexican authorities were not issuing plant-collecting permits, and Marker was advised not to venture into the area to collect the yam. Such advice had not stopped Marker before, and he did not let it get in his way now. Traveling by local bus, he eventually reached the area where he had been told the plant grew. There he collected two bags of the black foot-long roots from cabeza de negro (black head), as the yams were known locally.

  Back in Pennsylvania he extracted a very similar sapogenin to the sarsasapogenin from the sarsaparilla plant. The only difference was an extra double bond (arrowed) found in diosgenin, the sapogenin from the wild yam.

  Diosgenin, from the Mexican yam, differs from the sarsaparilla sapogenin, sarsasapogenin, only by an extra double bond (arrowed).

  The Marker degradation removed the unwanted side group, and further chemical reactions produced a generous amount of progesterone. Marker was convinced that the way to obtain sizable amounts of steroidal hormones at a reasonable cost would be to set up a laboratory in Mexico and use the abundant source in the Mexican yam.

  But if this solution seemed practical and sensible to Marker, it did not appear that way to the major pharmaceutical companies that he tried to interest in his scheme. Tradition and authority once more blocked his way. Mexico had no history of carrying out such complicated chemical syntheses, the drug company authorities told him. Unable to get financial backing from established companies, Marker resolved to enter the hormone-production business himself. He resigned from Pennsylvania State College and eventually moved to Mexico City, where, in 1944 and in partnership with others, he established Syntex (for Synthesis and Mexico), the pharmaceutical company that was to become a world leader in steroidal products.

  But Marker’s relationship with Syntex was not to last. Arguments over payments, profits, and patents led to his departure. Another company he established, Botanica-Mex, was ultimately bought out by Eu-ropean drug companies. By this time Marker had discovered other species of Dioscorea that were even richer in the steroid-containing diosgenin molecule. The cost of synthetic progesterone steadily decreased. These yams, once an obscure root used only as a fish poison by local farmers—the fish became dazed but were still edible—are now grown as a commercial crop in Mexico.

  Russell Marker, whose development of the series of chemical steps known as the Marker degradation allowed chemists access to abundant plant steroid molecules. (Photo courtesy of Pennsylvania State University)

  Marker had always been reluctant to patent his procedures, feeling his discoveries should be available to everyone. By 1949 he was so disgusted and disappointed both with his fellow chemists and with the profit motive that he now saw as driving chemical research that he destroyed all his laboratory notes and experiment records in an attempt to remove himself totally from the field of chemistry. Despite these efforts the chemical reactions Marker pioneered are today acknowledged as the work that made possible the birth control pill.

  SYNTHESIS OF OTHER STEROIDS

  In 1949 a young Austrian immigrant to the United States joined the Syntex research facilities in Mexico City. Carl Djerassi had just finished his Ph.D. at the University of Wisconsin, where his thesis work involved the chemical conversion of testosterone to estradiol. Syntex wanted to find a way to convert the now relatively abundant progesterone from wild yams to the cortisone molecule. Cortisone is one of at least twenty-eight different hormones isolated from the adrenal cortex (the outer part of the adrenal glands adjacent to the kidneys). It is a potent anti-inflammatory agent that is especially effective in treating rheumatoid arthritis. Like other steroids, cortisone is present in minute quantities in animal tissues. Although it could be made in the laboratory, such methods were very expensive. Synthesis required thirty-two steps, and its starting material, desoxycholic acid, had to be isolated from ox bile—which was not at all abundant.

  Using the Marker degradation, Djerassi showed how cortisone could be produced at a much lower cost from a plant source like diosgenin. One of the major stumbling blocks in making cortisone is attaching the double-bonded oxygen at carbon number 11 on the C ring, a position that is not substituted in the bile acids or sex hormones.

  Cortisone. The C=O at C#11 is arrowed.

  A novel method of attaching oxygen at this position was later discovered using the mold Rhizopus nigricans. The effect of this combination of fungi and chemist was to produce cortisone from progesterone in a total of only eight steps—one microbiological and seven chemical.

  After his success in making cortisone, Djerassi synthesized both estrone and estradiol from diosgenin, giving Syntex a preeminent position as a major world supplier of hormones and steroids. His next project was to make an artificial progestin, a compound that would have progesteronelike properties but could be taken orally. The aim was not to create a contraceptive pill. Progesterone, now available at a reasonable cost—less than a dollar a gram—was being used to treat women who had a history of miscarriage. It had to be injected and in fairly large doses. Djerassi’s reading of the scientific literature led him to suspect that substituting, on the D ring, a group with a carbon-to-carbon triple bond (≡) might allow the molecule to retain its effectiveness when swallowed. Another report had mentioned that removal of a CH3 group—the carbon designated as number 19—seemed to increase potency in other progesteronelike molecules. The molecule Djerassi and his team produced and patented in November 1951 was eight times more powerful than progesterone and could be taken orally. It was named norethindrone—the nor indicating a missing CH3 group.

  The structure of natural progesterone compared with the artificial progestin norethindrone

  Critics of the birth control pill have pointed out that it was developed by men to be taken by women. Indeed, the chemists involved in the synthesis of the molecule that became the pill were men, but as Djerassi, who is now sometimes known as the “Father of the Pill,” was to say years later, “Not in our wildest dreams did we imagine that this substance would eventually become the active ingredient of nearly half the oral contraceptives used worldwide.” Norethindrone was designed as a hormone treatment to support pregnancy or to relieve menstrual irregularity, especially where severe blood loss was involved. Then in the early 1950s two women became the driving force responsible for changing the role of this molecule from a limited infertility treatment to an everyday factor in the lives of countless millions of women.

  THE MOTHERS OF THE PILL

  Margaret Sanger, the founder of International Planned Parenthood, was jailed in 1917 for giving contraceptives to immigrant women at a Brooklyn clinic. Throughout her life she was an impassioned believer in a woman’s right to control her own body and fertility. Katherine McCormick was one of the first women to receive a degree in biology from the Massachusetts Institute of Technology. She was also, after the death of her husband, immensely wealthy. She had known Margaret Sanger for over thirty years, had even helpe
d her smuggle illegal contraceptive diaphragms into the United States, and had supplied financial help for the birth control cause. Both women were in their seventies when they journeyed to Shrewsbury, Massachusetts, for a meeting with Gregory Pincus, a specialist in female fertility and one of the founders of a small nonprofit organization called the Worcester Foundation for Experimental Biology. Sanger challenged Dr. Pincus to produce a safe, cheap, reliable “perfect contraceptive” that could be “swallowed like an aspirin.” McCormick supported her friend’s venture with financial backing and over the next fifteen years contributed more than three million dollars to the cause.

  Pincus and his colleagues at the Worcester Foundation first verified that progesterone did inhibit ovulation. Their work was done with rabbits; it was not until Pincus met another reproduction researcher, Dr. John Rock of Harvard University, that he realized similar results were available from human subjects. Rock was a gynecologist working to overcome fertility problems in his patients. His rationale for using progesterone to treat infertility assumed that blocking fertility by inhibiting ovulation for a few months would promote a “rebound effect” once the progesterone injections stopped.

  In 1952 the state of Massachusetts had some of the most restrictive birth control laws in the United States. It was not illegal to use birth control, but exhibiting, selling, prescribing, and providing contraceptives and even information about contraception were all felonies. This law was not repealed until March 1972. Given these legal constraints, Rock was understandably cautious in explaining his progesterone-injection treatment to his patients. As the procedure was still experimental, informed consent was especially necessary. So the repression of ovulation was explained but was stressed as a temporary side effect to the real aim of increased fertility.

  Neither Rock nor Pincus felt that injections of fairly large doses of progesterone would make a feasible long-term contraceptive. Pincus began contacting drug companies to find out if any of the artificial progesterones developed so far might be more potent in smaller doses and also effective orally. The answer came back: there were two synthetic progestins that fitted the requirements. The Chicago-based pharmaceutical company G. D. Searle had patented a molecule very similar to that synthesized by Djerassi at Syntex. Their norethynodrel differed from norethindrone only in the position of a double bond. The effective molecule is assumed to be norethindrone; stomach acids supposedly flipped the position of the double bond of norethynodrel to that of its structural isomer—same formula, different arrangement—norethindrone.

  The arrows point to the positions of the double bond, the only difference between Searle’s norethynodrel and Syntex’s norethindrone.

  A patent for each compound was granted. The legal question of whether one molecule that the body changes to another constituted an infringement of patent law was never examined.

  Pincus tried both molecules for the suppression of ovulation in rabbits at the Worcester Foundation. The only side effect was no baby rabbits. Rock then started cautious testing of norethynodrel, now given the name Enovid, with his patients. The fiction that he was still investigating infertility and menstrual irregularities was maintained, not without some degree of truth. His patients were still seeking help for this problem, and he was, for all intents and purposes, doing the same experiments as before—blocking ovulation for a few months to make use of the increase in fertility that seemed to occur, at least for some women, after this treatment. He was, however, using artificial progestins, administered orally and at lower doses than synthetic progesterone. The rebound effect seemed to be no different. Careful monitoring of his patients showed that Enovid was 100 percent effective in preventing ovulation.

  What was needed now was field trials, which took place in Puerto Rico. In recent years critics have denounced the “Puerto Rico experiment” for its supposed exploitation of poor, uneducated, and uninformed women. But Puerto Rico was well ahead of Massachusetts in terms of enlightenment on birth control. Although it had a predominantly Catholic population, in 1937—thirty-five years before Massachusetts—Puerto Rico amended its laws so that the distribution of birth control supplies was no longer illegal. Family planning clinics, known as “pre-maternity” clinics, existed, and doctors at Puerto Rico’s medical school as well as public health officials and nurses supported the idea of field testing an oral contraceptive.

  The women selected for the study were carefully screened and meticulously monitored throughout. They may have been poor and uneducated, but they were also pragmatic and practical. These women may not have understood the intricacies of the female hormonal cycle, but they did comprehend the perils of having more children. For a thirty-six-year-old mother of thirteen, eking out a living in a two-room shack on a subsistence farm, the possible side effects of a birth control pill would seem a lot safer than a further unwanted pregnancy. There was no shortage of volunteers in Puerto Rico in 1956; nor would there be for further studies done in Haiti and Mexico City.

  More than two thousand women participated in the trials in these three countries. Among them the failure-to-prevent-pregnancy rate was around 1 percent, compared with a failure rate among other forms of contraception of anywhere from 30 to 40 percent. The clinical trials of oral contraception were a success; the concept, proposed by two older women who had seen much of the hardship and misery of unfettered fertility, was workable. Ironically, if these trials had occurred in Massachusetts, even informing the subjects about the aim of the tests would have been illegal.

  In 1957 the drug Enovid was given limited approval by the Food and Drug Administration as a treatment for menstrual irregularities. The forces of tradition and authority still prevailed; though the pill’s contraceptive properties were definitely known, it was believed that women would be unlikely to take a daily contraceptive pill and that the relatively high cost (about ten dollars monthly) would be a deterrent. Yet two years after the FDA’s approval, half a million women were taking Enovid for their “menstrual irregularities.”

  G. D. Searle finally applied for the approval of Enovid as an oral contraceptive and formally obtained it in May 1960. By 1965 nearly four million American women were “on the pill,” and twenty years later it was estimated that as many as eighty million women worldwide were taking advantage of the molecule made possible by Marker’s experiments with a Mexican yam.

  The ten-milligram dose used during field trials (another point of present-day criticism of the Puerto Rican tests) was soon reduced to five milligrams, then to two milligrams and later to even less. Combining the synthetic progestin with a small percentage of estrogen was found to decrease side effects (weight gain, nausea, breakthrough bleeding, and mood swings). By 1965 Syntex’s molecule, norethindrone, through its licensees Parke-Davis and Ortho, a division of Johnson & Johnson, had the major share of the contraceptive market.

  Why was a birth control pill not developed for men? Both Margaret Sanger—whose mother died of consumption at fifty after having eleven children and a number of miscarriages—and Katherine McCormick played crucial roles in the development of the pill. Both believed that women should have contraceptive control. It is doubtful they would have supported research for a male pill. If the early pioneers of oral contraceptives had synthesized a molecule to be taken by men, would the criticism now be that “male chemists developed a method allowing men to have contraceptive control”? Probably.

  The difficulty with oral contraception for men lies in biology. Norethindrone (and the other artificial progestins) only mimic what natural progesterone tells the body to do—that is, to stop ovulating. Men do not have a hormonal cycle. Preventing, on a temporary basis, the daily production of millions of sperm is much more difficult than preventing the development of a once-a-month egg.

  Still, a number of different molecules are being investigated for possible birth control pills for men, in response to a perceived need to share the responsibility for contraception more equally between genders. One non-hormonal approach involves the mole
cule gossypol, the toxic polyphenol extracted from cottonseed oil that we mentioned in Chapter 7.

  Gossypol

  In the 1970s tests in China showed gossypol to be effective in suppressing sperm production, but uncertainty about the reversibility of the process and depleted levels of potassium leading to heartbeat irregularity were problems. Recent tests in both China and Brazil, using lower doses of gossypol (10 to 12.5 mg daily), have indicated that these side effects can be controlled. Wider testing is planned for this molecule.

  Whatever happens in the future with new and better methods of birth control, it seems unlikely that another contraceptive molecule could change society to quite the same extent as the pill. This molecule has not gained universal acceptance; issues of morality, family values, possible health problems, long-term effects, and other related concerns are still matters for debate. But there can be little doubt that the major change brought about by the pill—a woman’s control of her own fertility—led to a social revolution. In the last forty years, in countries where norethindrone and similar molecules became widely available, the birth rate has dropped, and women have gained more education and have entered the workforce in unprecedented numbers: in politics, in business, and in trade women are no longer an exception.

  Norethindrone was more than just a fertility-controlling medication. Its introduction signaled the beginning of an awareness, not only of fertility and contraception, but of openness and opportunity, allowing women to speak out (and do something about) subjects that had been taboo for centuries—breast cancer, family violence, incest. The changes in attitudes in just forty years are astounding. With the option of having babies and raising families, women now govern countries, fly jet fighters, perform heart surgery, run marathons, become astronauts, direct companies, and sail the world.