Perspectives in Health Magazine The Magazine of the Pan American Health Organization Volume 7, Number 1, 2002

Mexico's Pill Pioneer
by Gerald S. Cohen

Dr. George Rosenkranz at his home in Mexico City. His lifetime of work in pharmaceuticals has won him recognition, including Mexicos highest honor in the health field. (Photo ©Luis Corles)

An immigrant with a vision turned a tiny Mexico City chemical lab into an international pharmaceutical giant.

Fifty years after playing a leading role in the discovery of the oral contraceptive, George Rosenkranz, former CEO of the now- dissolved pharmaceutical powerhouse Syntex Corp., still avoids getting enmeshed in the politics of contraception. As far as he's concerned, the debate over the ultimate worth of the pill is best left to others.

In Mexico, however, where the 85-year-old chemist first came in 1945 to jump-start Syntex's synthesis of progesterone, there is little doubt where government leaders, health officials, and leading academicians stand. In the past year and a half, Rosenkranz has received three awards for his contributions to science and family planning. Among them are the prestigious Eduardo Liceaga Medal--the highest honor Mexico bestows in the health field--and awards from the University of Mexico and the Ministry of Health.

The discovery and marketing of the pill was arguably among the most profound important developments in recent pharmaceutical history. In Latin America, its rapid adoption from the early 1960s to the mid-1970s contributed significantly to the region's dramatic fertility decline. Between 1961 and 1964 alone, the number of U.S. women taking it doubled each year to 4 million users; today some 20 million American women are on the pill. Worldwide, some 300 million women have used the oral contraceptive since its inception.

Mexico's role in this global phenomenon was a result of Rosenkranz's and Syntex's work on the birth control pill. But the company's overall success also benefited the country's economy. Through its production of progesterone, Syntex became, by the mid-1950s, Mexico's fifth-largest exporter, attracting badly needed foreign currency to the still developing nation. "Syntex was an example of the importance of applying research to industry," says Guillermo Soberón, past president of the University of Mexico and a former minister of health. "It is something we are still lacking in Mexico--the opportunity to encourage industrial research."

Equally important were the company's investments in education. During Syntex's early years, when not a single Mexican had acquired a Ph.D. in chemistry, Rosenkranz used Syntex funds to underwrite an advanced degree program in organic chemistry at the University of Mexico's Institute of Chemistry.

"Syntex was fundamental for the development of the Institute of Chemistry at the university," says Soberón. "Several of the people who worked with Syntex also worked at the institute, and their research guided students on their doctoral theses." A number of the researchers nurtured by Syntex have gone on to prominent roles in Mexico's scientific community. Moreover, says Soberón, "these researchers developed another generation of researchers."

From Zurich to Havana

Rosenkranz, a scientist and businessman, did not set out to solve the entrenched sociological problems of family planning and population growth. But he has indisputably clearly helped move these issues forward, and his lifetime of work in the synthetic production of steroids has helped relieve the suffering of millions afflicted with arthritis, Addison's disease, bursitis, and other ailments.

Rosenkranz circa 1950, draws a diagram of a steroid molecule. With other Syntex Corp. scientists, he won the high-stakes race to efficiently synthesize cortisone. (Photo courtesy George Rosenkranz)

Few get such an opportunity to affect the lives of so many. And many who have achieved so much would be content in later life comfortably resting on their laurels. But Rosenkranz is not among them. Throughout his lifeIn all his pursuits, he Rosenkranz has been driven by ambition and curiosity, but also by a sense of mission and service. He has been a dreamer and a pragmatist, a protégé of Nobel laureates and a mentor to followers of his own. In recent years, he has used his prestige to argue for increased government investment in science and research in Mexico and has become a key adviser to a joint government and private enterprise that will apply genomic research to medicine.

Discovering what makes a man like Rosenkranz tick does not come easily. Throughout his life, Rosenkranz he has been a private individual who has granted few interviews. That sense of privacy was reinforced in his senior years when his wife, while attending a bridge match with him in Washington, D.C., was kidnapped at gunpoint by three individuals demanding a reported $1 million ransom. All ended well, but one gets the sense that Rosenkranz, who today splits his time between Palo Alto, Calif., and Mexico City, has learned not to reveal more than necessary about himself or his family. Still, one can begin to understand him by examining the body of his work, the company he built, and the manner in which he has derived--and continues to derive--energy for his many projects.

Rosenkranz's career began taking shape just as the storm clouds of World War II were starting to gather in Europe. The Budapest-born scientist earned his chemical engineering degree in 1938 and a doctorate in technical sciences in 1940 at the renowned Swiss Federal Institute of Technology in Zurich. It was one of those places where, as Rosenkranz puts it, "a number of Nobel Prize winners were running around." He was fortunate to be appointed research assistant to one of these, Leopold Ruzicka, a Nobel Prize winner known for his work in steroid chemistry. The relationship that developed between Rosenkranz and Ruzicka was more than just that of student and teacher; Ruzicka was a mentor to Rosenkranz but also a guardian of sorts. "He was protecting the Jews in Zurich," Rosenkranz recalls.

Although Switzerland was a relatively safe place to be in those unsettling years, Nazi sympathizers were still a menacing presence. Rosenkranz and about six of his Jewish colleagues did not feel entirely comfortable in the country; even worse, they understood that their presence could have adverse effects on Ruzicka. "There was a lot of pressure on him, so we got together and we decided to leave Switzerland to protect him."

Most of the students came to the United States, but Rosenkranz accepted a position in Quito, Ecuador, as chairman of an organic chemistry department. He took a boat first to Havana, where he would have to wait three weeks for passage to Ecuador. The Ecuador-bound vessel never came, and then Pearl Harbor intervened. It seemed the war was following Rosenkranz. Then President Fulgencio Batista of Cuba issued a decree allowing all refugees to stay and work, so Rosenkranz decided to remain and took a job with the country's largest pharmaceutical firm, where he became director of research.

Over the next four years, Rosenkranz maintained an interest in making steroid hormones, which were understood to be critical for such key physiological functions as metabolism, growth, and sexual reproduction. It was also known that hormone deficiencies could lead to a number of illnesses, including rheumatoid arthritis, infertility, and Addison's disease. One of the biggest challenges with steroid research, however, was that these hormones were enormously expensive because they had to be extracted from animal glands. Huge numbers of animals had to be slaughtered to derive small quantities of the substance.

Rosenkranz was familiar with the research of Russell Marker, a maverick and mercurial chemist from Pennsylvania State University, who in the 1930s became convinced that certain plants could be an abundant and easy-to-convert source of steroid raw materials. Marker had spent a decade researching sapogenins, a group of toxic steroids that could be obtained by degrading plant compounds known as saponins. Sapogenins have a chemical structure similar to cholesterol, the starting material for steroids in the human body. In 1939, Marker figured out the exact molecular structure of sapogenins and devised a method for converting the sapogenin molecule into a molecule identical to the pregnancy hormone progesterone.

A trick with yams

An inedible yam called cabeza de negro, which grew wild in Mexico, proved to be a very practical source for a sapogenin called diosgenin. On one trip to Mexico, Marker gathered 10 tons of the root, succeeded in producing about three kilograms of progesterone, and then searched for partners to fund his work. After Parke-Davis rejected him, he pored through a Mexico City phone book and located Laboratorios Hormona. The tiny firm founded by two European refugees, Emeric Somlo and Frederick Lehmann, understood the enormous financial potential of the process. On Jan. 21, 1944, they incorporated Syntex, with the intent of using Marker to help synthesize pure crystalline progesterone for pharmaceutical companies. With an initial capitalization of $100,000, Syntex was able to construct additional laboratories and synthesize 30 kilograms of progesterone within the first 12 months. Before the year was out, however, Marker had a disagreement with his partners, pulled up stakes, and took key components of the synthesis process with him.

Rosenkranz with his Syntex staff and the cabeza de negro yam, which yelded the raw material needed for the synthesis of cortisone. (Photo courtesy George Rosenkranz)

Meanwhile, Rosenkranz had been tinkering with some Cuban yams. An edible variety, they apparently lacked the toxic sapogenins critical to a successful synthesis. "Then I imported to Cuba from Mexico the sarsaparilla root and made some small quantities of progesterone," he says. Word of Rosenkranz's work reached Somlo and Lehmann from business associates who had been traveling through Cuba. Eager to restart their stalled chemical process, Somlo and Lehmann invited Rosenkranz to Mexico City for a job interview.

The date of the interview was Aug. 6, 1945, the day the Enola Gay dropped the first atom bomb on Hiroshima. Rosenkranz, and most everyone else in the Western Hemisphere, was at first unaware of the event. In Mexico City it was a beautiful day. "I saw the blue sky, the volcano, and heard this music outside my hotel window," he recalls. "An organ grinder was playing a hand organ downstairs. This was fantastic. I immediately fell in love with Mexico."

The job interview was not exactly what Rosenkranz had expected. It soon became clear that Marker had left his former partners in a fix. Critical ingredients for the synthesis were hidden or unmarked, and the process itself was a mystery to Somlo and Lehmann. As a test, the partnersy gave Rosenkranz a lab coat and asked him to perform the last step in the progesterone synthesis process, which was to make the catalyst aluminum isopropylate. Rosenkranz had done the procedure many times before; it simply required starting a reaction between aluminum and isopropyl alcohol by dipping aluminum foil in mercury chloride. "It was a little trick that anybody with my training who worked in a laboratory would know," Rosenkranz says. "You need the catalyst to start the reaction, and the reagent is necessary to make the progesterone." All went well, and Somlo and Lehmann were flabbergasted. "They thought I was Houdini," Rosenkranz says.

The owners of Syntex pointed to a stack of unfilled orders for progesterone and offered him a job on the spot. Although Syntex was a risky proposition at that point, the future wasn't so bright in Cuba either. Rosenkranz found himself frustrated by the unavailability of critical supplies. "I only had hydrochloric acid, sulfuric acid, benzene, and alcohol," he says. "I had to make my own ether." After considering their proposition, which included a share of the profits and stock options, he turned his thoughts to the potential benefits of mass-producing steroids. He accepted their offer. In the next breath he called Havana and proposed marriage to his Viennese-born girlfriend, who remains his wife to this day. Two months later Rosenkranz began fulfilling orders for progesterone. "I decided I wanted to make Syntex the Dupont of Mexico," he says. "Little did I know."

The steroids race

An early corporate portrait. In later life, Rosenkranz has used his prestige to argue for increased government investment in science and research in Mexico. (Photo courtesy George Rosenkranz)

The first step in achieving his high ambitions for Syntex was to unravel the mysteries of synthetically manufacturing other major steroids considered so critical to disease prevention. For about a decade, three teams of chemists in Switzerland, at Columbia University in New York, and at the Mayo Clinic in Rochester, Minn., had been working on isolating steroid hormones found in the adrenal glands. The U.S. government was intensely interested in learning more about this class of hormones, called corticoids, and in 1940 began funding cooperative research in this important field. In 1946, scientists at Merck & Co. Inc. had succeeded in synthesizing cortisone from animal-sourced materials through a 36-step process considered too tedious and expensive for industrial purposes. The stakes were raised on finding a better synthesis process when a chemist at the Mayo Clinic revealed in 1948 that he had successfully used small doses of the Merck-produced cortisone to heal severely arthritic patients. He underscored the miraculous benefits of the compound by distributing movies of bedridden patients who were able to get up and dance after only a day of cortisone treatment.

The movies helped set off a race to efficiently synthesize cortisone--something that approached the 1950s equivalent of the space race. Newsmagazines followed closely the progress of the competing firms. The major players were two research teams from Harvard University, a team from Merck, and a group of upstarts from Mexico City. Since his arrival at Syntex, Rosenkranz had been assembling a dream team of young scientific prodigies from around the world who one day would develop international reputations of their own. Among them were Carl Djerassi and Alex Zaffaroni. After synthesizing progesterone, Rosenkranz had engaged them in the synthesis of other steroids. In 1946, the Syntex team synthesized a substance closely related to the male hormone testosterone; in 1949 they manufactured the female hormones estrone and estradiol. The discoveries were good practice for the cortisone race.

Using diosgenin as a starter material, the Syntex scientists worked full tilt to develop a breakthrough. At one point in 1950-51, the team worked two shifts, seven days a week to keep up with the competition. In a photo finish, Syntex won the race in the summer of 1951 over its better-funded and more prestigious U.S. competitors. Life magazine announced the victory with the headline "Cortisone from a Giant Yam: Scientists with Average Age of 27 Find Big Supply in Mexican Root." Harper's Magazine wrote that the cortisone race "also underscores a point often overlooked in a big-money age. Big minds rather than big research budgets lead to big discoveries."

The rush to market

The cortisone discovery put Syntex on the map. Upjohn just a few months later discovered a one-step process for manufacturing an effective and simpler compound called hydrocortisone. But the process relied on tons of progesterone, a quantity that could be satisfied only by Syntex's patented process. Upjohn's discovery translated into an immediate infusion of $5 million in cash for Syntex.

A group of dignitaries listens as Rosenkranz (far right) explains a chemical process at Syntex's headquarters in Mexico City in the 1950s. (Photo courtesy George Rosenkranz)

These many months of work also set up Rosenkranz's team for the discovery of the birth control pill. Progesterone, testosterone, estrone, estradiol, and cortisone were all close relatives of a soon-to-be-synthesized compound called norethindrone. In October of 1951, Luis Miramontes, a college student under the direction of Rosenkranz and fellow researcher Carl Djerassi, synthesized norethindrone, the active ingredient for what would become the oral birth control pill. Syntex patented norethindrone in November of that year. It would take nine more years of experimentation and patient trials for an FDA-approved pill to make it to market, and it wouldn't be Syntex's product.

During this period, Rosenkranz recalls that religion and politics, rather than science, drove scientific decisions. "I went around Europe and the world offering the contraceptive, but nobody wanted it," he says. Because Syntex did not have the resources to market the product internationally, it first offered to become the bulk supplier of norethindrone to Parke-Davis. But in 1956, the decision by a company to manufacture an oral contraceptive meant risking a boycott of its whole product line by religious opponents. Ultimately, the big drug manufacturer backed away from the deal.

Meanwhile, G.D. Searle and Co. moved ahead with a compound remarkably similar to norethindrone, patented its discovery, and went to market with it in 1960. In the end, it made little difference which company got there first. A few years later, Syntex was able to capture the majority of the market share through licensing agreements for norethindrone with Ortho, Eli Lilly, and a once-again-interested Parke-Davis. Syntex also brought its own oral contraceptive to the market.

But the pill was neither the first nor the last of Rosenkranz's major accomplishments at Syntex. His team attracted the interest of Wall Street investor Charles Allen, who with his brother in 1956 purchased Syntex Corp., parent company of the Mexican and U.S. Syntex entities, and took it public in 1958 with a stock authorization of 2 million shares, of which 1.2 million were immediately issued. Rosenkranz, named one year earlier as president and CEO, was retained.

In 1964, Rosenkranz decided to move the company to Palo Alto so that it could be closer to its major market. In the midst of the Palo Alto expansion, Syntex experienced one of the greatest stock runs of the decade. After announcing a three-for-one split of stock on July 31, 1963, Syntex stock soared. Shares that had sold for only $5.75 at the beginning of the year rose as high as $227.50 by mid-October. On November 1, Syntex stock rose $21, the year's most active single-day rise on any major exchange.

With most of the major advances in steroidal research behind it, Rosenkranz realized that if the company were to continue to prosper, it would need to expand into other areas. A team of researchers began exploring possibilities for a nonsteroidal anti-inflammatory drug for the systemic treatment of rheumatoid arthritis and osteoarthritis. The result of this research was another blockbuster drug, Naprosyn. Over the next few years, the FDA cleared Naprosyn for use in treatment for a wide range of illnesses including osteoarthritis, bursitis, a group of soft tissue injuries, and juvenile arthritis. Five years later, naproxen sodium was introduced to the U.S. market as Anaprox. By 1983 the two drugs were the largest-selling nonsteroidal anti-inflammatories in the world. Both helped boost Syntex's annual sales to $1 billion in 1987. Alleve, a pain reliever used for arthritis, muscle pain, and menstrual cramps, followed a few years later, making Syntex's transformation into a major pharmaceutical company complete.

The lives of corporations, however, are not very different from the lives of individuals; in a moment, things can change. The fortunes of Syntex shifted dramatically in December 1993 when its patent protection on Naprosyn and Anaprox expired. Syntex's profits declined significantly as cheaper generic versions flooded the market. With falling profits but significant assets, the company became an attractive takeover target.

An era ends

Rosenkranz holds the first box of Syntex's oral contraceptive "Norinyl" (Photo courtesy George Rosenkranz)

In 1994, Syntex Corp. was acquired by pharmaceutical giant Roche Holding Ltd. of Basel, Switzerland. The takeover marked the end of an era: Rosenkranz still refers to it as "the unhappy end of the Syntex saga." But the saga is a remarkable one. In a relatively short period, and largely because of Rosenkranz's vision, a $100,000 investment in a tiny Mexico City chemical house was transformed into an international pharmaceutical giant worth $5.3 billion.

Rosenkranz successfully challenged the science community's heaviest hitters in the development of cortisone. He took on the social and religious critics of contraception with the development of the pill, thereby injecting a new sense of hope into desperately needed family planning initiatives in the developing world. He helped nurture a generation of leaders in chemical research and business in Mexico and the United States. By any measure, he not only achieved his dream of creating the Dupont of Mexico, but also helped heal countless people along the way.

Today, instead of reveling in the successes of the past, Rosenkranz is setting his sights on other challenges. He wants to participate in the deciphering of the human genome, to help establish Mexico as a force in this new frontier and to keep his hand in any number of business ventures that continue to swirl around him at a pace that would make a man 30 years his junior dizzy.

Indeed, anyone looking for the secret of eternal youth would be wise to consult Rosenkranz. Once a tennis and ski enthusiast, he continues to lift weights and work out twice a week at the gym. To keep mentally active, he treats his brain like any other muscle in his body. "The most important thing is mental exercise," he says. "According to the New England Journal of Medicine, the onset of Alzheimer's can be delayed by 10 years through strong intellectual activity."

So how does Rosenkranz (who speaks six languages) exercise his mind? "I'm still playing bridge, not as much as before, but better than ever," he says. Rosenkranz has authored 14 books on contract bridge and won 12 U.S. National Bridge Championships and some 100 Mexican National Championships playing against the likes of actor Omar Sharif, who once led the Egyptian team. He was inducted into the Bridge Hall of Fame in 2000 and recently wrote an article about how to cope with aging at the bridge table.

He also stays as close as he can to the rapidly changing world of scientific discovery by spending an hour a day on his home computer and reading scientific journals. His longtime friend and business associate Alex Zaffaroni, who founded his own tremendously successful drug delivery company, lives down the block in Palo Alto. Zaffaroni continues to bounce ideas off Rosenkranz, who plays the role of devil's advocate for Zaffaroni just as he did in Syntex's halcyon days.

Rosenkranz remains involved in scientific pursuits as a member of the board of Digital Gene Technologies Inc., of La Jolla, Calif., a company active in genomic research. It is through DGT that Rosenkranz has exercised his interest in what he is sure is the next great frontier of scientific discovery. To position Mexico for a new era, Rosenkranz has successfully encouraged the government to develop a new authority dedicated to promoting genomic research. The authority will include the Ministry of Health.

He also is working teaming up with another former Syntex colleague from his Syntex days in a Menlo Park, Calif.,new venture called Pherin Pharmaceuticals. The company that is experimenting with a class of compounds called pheromones, which may have potential for treating a number of central nervous system disorders. With a trace of amusement, Rosenkranz notes that he synthesized the first compound of this class about 50 years ago. "Thus my scientific life built on steroids has come full circle," he says.

All this keeps a man who has authored more than 150 publications and whose name is on 143 patents going at a steady pace, even in his 80s. "I have a tremendous intellectual curiosity and I am interested in everything," he says. Asked if now might be the time at least to start thinking about retirement, he answers firmly, almost defiantly, "I won't retire--ever!"

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