Russell Marker during his years at Pennsylvania State University Courtesy of Pennsylvania State University

Despite his advisor's lack of optimism, Marker did indeed go on to make tremendous scientific contributions throughout his career. While not the only scientist or social visionary involved, Marker's work formed the scientific cornerstone for the development of oral contraceptives, among the most socially significant scientific discoveries ever made. Yet despite such professional achievements, Marker's story remains marked by the combination of independence, good fortune, and ingenuity that led him to walk away from a Ph.D. because of a disagreement over coursework.

In the words of Steven Weintraub, the Russell and Mildred Marker Professor of Natural Products Chemistry at Pennsylvania State University, "There are more stories told about Russell Marker than perhaps any chemist. Although many of these stories are apocryphal, they are so fascinating that most of us cannot bear to stop repeating them. This is the oral history of our profession that we pass to our colleagues and our students. They are the campfire stories that bind our profession together."

Following his less-than-glorious send-off from the University of Maryland, Marker's interest in hydrocarbon research led him to Ethyl Corporation. While at Ethyl, he developed an octane rating system for gasoline that is still used today. However, after a few years Marker's chemical interests changed, and he left Ethyl to work as an organic chemist at the Rockefeller Institute. Here too he met with success; over a six-year period he produced many publications focusing on molecular configurations and their relationship to reaction chemistry. Eventually, Marker's background in hydrocarbon chemistry and molecular orientation led him to the developing field of steroid research. In 1938, he accepted a funded position at Pennsylvania State University.

The power of hormones

Figure 1: An overview of the menstrual cycle. Progesterone is critically important in controlling this progression of events and thus the ability to medically manipulate progesterone led to the development of birth control. (Click on image to see larger version) Courtesy of Holistic Online

Of particular interest at this time in chemical history were the recently discovered sex hormones, or androgens, molecules such as testosterone, estrogen, and progesterone (see Figure 1). Of these, progesterone was perhaps the most interesting because it is the chemical precursor for another class of steroids, the glucocorticoids. Glucocorticoids and androgens are instrumental in controlling many of life processes. Metabolic disposal of carbohydrates, proteins, and lipids, inflammatory responses vital to a functioning immune system, maintenance of blood hydration, pH and salt levels, as well as sexual development and function all rely on the proper functioning of various steroids.

The vast power of such hormones was not lost on physicians, and by the 1930s, progesterone was used to treat menstrual disorders, problem pregnancies, and gynecological cancers. However, progesterone was so expensive to purchase that both research and medical endeavors were often stymied. The only known way to isolate the hormone involved laborious and inefficient synthesis exploiting the byproducts of cholesterol oxidation. In a price comparison, at today's market value, gold sells for about $11 a gram; in the 1930s, progesterone sold for $80 a gram. And so, despite the potential medical benefits of steroid hormones, progress in the field remained frustratingly slow.

It may have been his unusual academic background or work experience that contributed to Russell Marker's breakthrough in the field of hormone synthesis. In 1938 he presented a chemical hypothesis that contradicted prevailing chemical beliefs of the time. He proposed that the side chain of sarsasapogenin, a plant steroid derived from the sarsparilla plant, was not chemically inert but actually chemically reactive. As a result, if chemical groups were removed from the sarsasapogenin side chain, then what remained was no longer sarsasapogenin but progesterone (see Figure 2). In a series of reactions now known as Marker degradation, Marker had found a way to synthesize progesterone.

Figure 2: The molecular structure of diosgenin, the precursor for progesterone isolated from yams Courtesy of www.friedli.com/herbs/phytochem/ glycosides.html

There was only one problem - sarsasapogenin was also extremely expensive. However, rather than give up on his idea, Marker began studying botany, trying to find a less-expensive chemical relative of sarsasapogenin with which to further his studies. His search led him south, to the Mexican-American border in the Southwest, and finally into Mexico itself.

Figure 3 : Veracruz, Mexico, in the eastern region of Mexico, was the source of Marker's wild yams (Click on image to see larger version) Courtesy of http://shunya.net/Pictures/Mexico/mexico-map.jpg

"After I was convinced that Parke-Davis would not go into it, I tried other companies to get support. For instance, I tried Merck and they said that since Parke-Davis turned me down they would not go into it. … Then I decided that I was going to have to go into it myself."

And so, with the determination that had once led him to walk out on a Ph.D., Marker resigned his position at Penn State, withdrew all of his savings, and moved to Veracruz. He soon became an expert on yams, harvesting 10 tons of them from the Mexican jungle. The yams were dried and reduced to a syrup that was easily transported back to the United States. Marker borrowed a friend's lab to convert his yam syrup into three kilograms of progesterone, at that time the largest batch ever produced, with a 1943 market value of about $240,000. Convinced that his idea was commercially viable, Marker decided to return to Mexico in search of partners in industry.

Arriving in Mexico City, he turned to the phonebook. In 1944 a small company called Syntex was formed as a result of a partnership between Marker, Emerik Somolo, a Hungarian immigrant to Mexico, and Dr. Federico Lehmann, a German-trained scientist. Unfortunately, this relationship was not to last. Following disputes over profits, Marker pulled out of Syntex by the end of 1945 and established his own company. For personal reasons he retired from this position, and from chemical research itself, in 1949 at the age of 47.

By 1950 two additional discoveries had been made. First, the "magic substance" first described in 1921 was properly identified as progesterone. Second, following the achievements of Russell Marker and succeeding chemists, progesterone had become one of the cheapest and most readily available of all hormones. Thanks to Syntex, the price of progesterone had plummeted from $80 to $1 per gram.

These discoveries became reality just as social consciousness was beginning to explore the concept of contraception; hormonal manipulation of the female reproductive system seemed an ideal possibility for birth control. However, progesterone itself wasn't the best candidate because it required injection; an orally-active mimic of progesterone was a better alternative.

In 1951, Carl Djeressi, the scientist who succeeded Marker at Syntex, filed for a patent on a compound he called norethindrone, a modification of progesterone. In 1953, the pharmaceutical company G.D. Searle obtained a patent on the work of Frank Colton, a chemical variant they dubbed norethynodrel. The irony of this dual discovery is that neither scientist had a birth control pill in mind when developing the compounds. There was greater interest in using progesterone mimics to synthesize cortisol, a compound already in use as a treatment for inflammatory disease.

However, eventually the connection was made between orally active "progesterone" and birth control. After several years of testing, G.D. Searle obtained the first FDA patent for an oral contraceptive in 1960. This was followed in 1962 by a Syntex patent now marketed as part of Johnson & Johnson. Norethindrone, the chemical that got its start in a small lab in Mexico, is the active ingredient in nearly half of all oral contraceptives used today.

Oral Contraceptives - "the Pill" that developed out of Marker's work Courtesy of University of Arizona Campus Health

"In the U.S., I believe, this led to more certainty in women's careers and was part of women's really growing in stature and influence in the professions.Internationally, I think, it also helped women with the sense of control over their lives and is still part of transformations in women's independence and growth in education and leadership."

In addition, beyond social influences, the scientific relationships formed in Mexico have led to beneficial growth in that country's research endeavors and scientific community. In 1951, following the patent on norethindrone, Fortune magazine headlined an article: "Syntex makes the biggest technological boom ever heard south of the border." Further developments needed to sustain scientific growth led to the establishment of what is now Mexico's leading research institute, the Instituto de Quimica of the National University. Noriega Bernechea, the president of the Mexican Sociedad de Quimica, says, "the debt of gratitude that Mexican research and education owe Syntex cannot be overshadowed by anything."

It would be impossible to tally the lives affected by Russell Marker's contribution to chemistry. It would also be impossible to estimate the odds that his discovery and the steps it entailed - walking out on a Ph.D., conducting three completely different kinds of chemical research before age 40, resigning a prestigious faculty position, and spending life savings in pursuit of Mexican yams - would be made at all. And that is what makes science fun. Great discoveries are often made by those willing to see things in a slightly different way. Even a remote, inedible wild tuber has value for those willing to search for it.