Percy Lavon Julian, Russell Earl Marker, and Carl Djerassi
Percy Julian. Gift of Ray Dawson, CHF Collections.
In the 1930s chemists recognized the structural similarity of a large group of natural substances—the steroids. These include cholesterol, bile acids, sex hormones, and the cortical hormones of the adrenal glands. The medicinal potential of various steroids quickly became obvious, but extracting sufficient quantities of steroids, which exist in minute amounts in animal tissue and fluids, was prohibitively expensive. As with other scarce or difficult-to-isolate natural products, chemists were called upon to mimic nature by creating these steroids in the lab, and later by modifying them to make them safer and more effective as drugs. Chemists found starting materials in certain plant substances that were also steroids. Percy Lavon Julian (1899–1975), Russell Earl Marker (1902–1995), and Carl Djerassi (b. 1923) were among those scientists who participated actively in the synthesis and large-scale production of steroids—both cortisone and the sex hormones—from plant compounds.
Julian was born in Montgomery, Alabama, the son of a railway mail clerk and the grandson of slaves. In an era when African Americans faced prejudice in virtually all aspects of life, not least in the scientific world, he succeeded against the odds. Inadequately prepared by his high school, he was accepted at DePauw University in Greencastle, Indiana, as a sub-freshman, meaning that he had to take high school courses concurrently with his freshman courses. Majoring in chemistry, he graduated as valedictorian of his class in 1920. After graduating, he was a chemistry instructor at Fisk University for two years before winning an Austin Fellowship to Harvard University, where he completed a master’s degree in organic chemistry. After Harvard, he returned to teaching at West Virginia State College and Howard University.
Russell Marker. Courtesy Penn State University Archives, Eberly Family Special Collections Library.
In 1929 Julian traveled to the University of Vienna, Austria, to begin doctoral studies on the chemistry of medicinal plants. Two years later, with a doctoral degree in hand, he and a Viennese colleague, Josef Pikl, took positions back in the United States at Howard, and two years later moved to DePauw. There they accomplished the first total synthesis of physostigmine, the active principle of the Calabar bean, used since the end of the 19th century to treat glaucoma. Physostigmine, an alkaloid, eases the constriction of outflow channels from the eye’s aqueous humor to relieve high pressure there, which, if left untreated, damages the retina and eventually causes blindness.
Meanwhile researchers in many countries were seeking innovative and cost-effective ways to synthesize steroids, including cortisone and the sex hormones. German chemists discovered that the steroid stigmasterol, which Julian had obtained as a by-product of the physostigmine synthesis but was also obtainable from soybeans, could be used in the synthesis of certain sex hormones, including progesterone, a female sex hormone that was important in helping pregnant women avoid miscarriages. In pursuit of this lead, in 1936 Julian wrote to the Glidden Company in Chicago, requesting samples of their soybean oil. Through a series of events he wound up being hired by Glidden instead, as their director of research in the Soya Division, where he set about figuring out ways to make new products from soybeans.
Carl Djerassi at Syntex in 1951, with his assistant Arelina Gonzalez. Courtesy Professor Carl Djerassi.
Three years after arriving at Glidden, Julian learned from plant workers that water had leaked into a tank of purified soybean oil and formed a solid white mass. Immediately identifying the substance as stigmasterol, he realized he had stumbled upon a method for producing large amounts of the steroid from soybeans. Though scientists already knew how to synthesize progesterone from stigmasterol, they didn’t have a method for doing it on a massive scale. Now with large quantities of stigmasterol at hand, he was able to develop an innovative industrial process for converting it to progesterone in bulk, producing five to six pounds of progesterone per day (worth thousands of dollars in those days). Soon other sex hormones were in production.
In 1948 scientists at the Mayo Clinic announced their landmark discovery of cortisone, which had remarkable effects on rheumatoid arthritis, and Julian jumped into the exciting competition to synthesize cortisone inexpensively. Cortisone is a cortical hormone of the adrenal gland. Julian developed a new synthesis for a related substance (called “Substance S”) also present in the adrenal cortex and differing from cortisone by only an oxygen atom. From this substance he was able to synthesize both cortisone and hydrocortisone. Hydrocortisone and its derivatives today are more widely prescribed than cortisone products, and most industrial syntheses still begin along the same route that Julian pioneered.
Julian remained at Glidden until 1954, when he founded his own company, Julian Laboratories of Franklin Park, Illinois, and Mexico City (which he eventually sold to Smith, Kline and French). Throughout his life he was socially active in groups seeking to advance conditions for African Americans, helping to found the Legal Defense and Educational Fund of Chicago and serving on the boards of several other organizations and universities. (For more on Julian’s life and works, see Science Alive! The Life and Science of Percy Julian.)
Like Julian, Russell Marker turned to plant substances from which to synthesize steroidal hormones. Marker was born in 1902 in a log cabin on a farm near Hagerstown, Maryland, where his father was a sharecropper until he could afford to purchase his own land. Although his father wanted him to stay on the farm, his mother encouraged him to pursue a college education. In this she prevailed. Since the high school that Marker attended offered only a commercial program, he had not taken the preparatory subjects necessary for admission to the University of Maryland, but he did well in summer-school mathematics and English courses and was accepted to the regular degree program in the fall of 1919. His introduction to the subject of chemistry, unlike that of most other students, came in college, where he had to catch up with his classmates’ familiarity with simple equipment and the chemical symbols. In the organic chemistry laboratory he demonstrated outstanding skill in carrying out difficult organic syntheses, a talent that would serve him well throughout his career. On completing his bachelor’s degree, he continued at the university as a graduate student, writing both a master’s thesis and a doctoral dissertation. When he learned that he lacked required courses in physical chemistry, he left without completing the degree. His interest was in organic chemistry, and he thought he knew all the physical chemistry he needed.
Setting out in industry, Marker worked for about half a year as an analytical chemist at the Naval Powder Factory in Indian Head, Maryland. In 1926 he obtained a more research-oriented position at the research laboratory of the Ethyl Gasoline Corporation in Yonkers, New York. This company had recently been founded to produce tetraethyl lead, the gasoline additive that increased the fuel efficiency of gasoline engines and made usable the petroleum fractions previously burned or vented into the atmosphere. (Fifty years later the Environmental Protection Agency instituted the reduction of tetraethyl lead in gasoline as hazardous to the health of gasoline attendants and others who came into close contact with its fumes.) At Ethyl, Marker helped develop the standard gasoline against which “octane” is rated. Meanwhile word spread of his reputation as a wizard at synthesizing organic chemicals that other scientists found difficult to obtain, and he was asked to synthesize a particular compound for a scientist working at the Rockefeller Institute in New York City. After Marker successfully completed this task, Simon Flexner, the institute’s president, invited him to take a position at this prestigious biomedical research facility in 1928.
Although Marker’s major responsibility at the institute was to synthesize compounds for other scientists, he was also encouraged to carry out his own research projects. In the early 1930s he became interested in the emerging field of hormones. When he declared his interest in synthesizing hormones from plant materials, he came into conflict with the powers at the institute. One of the institute scientists, working on the plant steroid present in the sarsaparilla root, had supposedly “proved” that the molecule simply could not be converted into a chemical intermediate to a hormone. In a confrontation with Flexner, who praised Marker’s performance in general but would not agree to a research project that looked like it was going nowhere, Marker threatened to leave the institute if he could not have his way.
And leave he did, in 1934, for a much lower-paying position in the chemistry department at Pennsylvania State University. Here he was welcomed by a department chairman who had known and admired Marker’s work on hydrocarbons at Ethyl. With the aid of reagents and intermediates supplied by Parke, Davis and Company, Marker set to work repeating the experiments done on steroids by the great German and Swiss scientists like Adolf Butenandt and Leopold Ruzicka. Marker’s first big success was in isolating pregnanediol from bull’s urine. From this substance he synthesized progesterone.
Meanwhile Marker was able to show that the structure of one of the sapogenins, plant sterols modified by treatment with acid, was not that reported by leading chemists in Germany and the United States—and that the compound was not inert. He then proceeded to transform the sapogenin from sarsaparilla root, sarsasapogenin, into a molecule identical in structure to that of progesterone. Marker turned next to a substance called diosgenin, obtained from a member of the Dioscorea plant group, a genus containing yams, and transformed it into progesterone. This success sent Marker off on a wide-ranging search for species of Dioscorea with sufficiently large roots to make harvesting and processing the material economical. In 1942 he searched for and found in the wilds of Mexico the cabeza de negro, a yam with roots that can weigh up to a hundred pounds each. At the time Mexico seemed about to join the Axis powers in World War II, which made his adventure appear risky indeed to officials at the U.S. embassy in Mexico City.
Back in the United States with samples of dried root, Marker tried unsuccessfully to convince the president of Parke, Davis that the company should rely on diosgenin as the starting material for their manufacture of hormones. Drawing half his meager savings from the bank, Marker returned to Mexico to pursue the development of diosgenin on his own. He made arrangements for the harvesting, drying, and extracting of a syrup from the roots and its export to the United States to a small laboratory, which turned it into what amounted to three extremely valuable kilograms of progesterone.
Marker tried to interest financial backers in his venture—without success, until he found Laboratorios Hormona in Mexico City. This company, begun in 1933 to extract hormones from animal sources, was founded by Emeric Somlo, a Hungarian lawyer-entrepreneur who had first come to Mexico in the 1920s. In March 1944, Marker, Somlo, and Frederico Lehmann, Hormona’s chief chemist, formed a new company called Syntex. Somlo and Marker did not get along well, and in May 1945 Marker left Syntex, taking his processes with him. He founded Botanica-Mex, which also made hormones from Dioscorea and did so with some success. But in 1949 Marker left Botanica-Mex, which survived for decades as a subsidiary of successive international companies.
In 1949, at the age of 47, Marker left chemistry altogether to set up a business making reproductions of 18th-century silver objects. He had become a legend in his own time. He first reappeared in the chemical community in 1969 when the Mexican Chemical Society presented him with an award. Some at the ceremony presumed that this was a posthumous award and were shocked to see Marker walk in. In fact he lived another two-and-a-half decades, occasionally attending symposia honoring him and his chemical colleagues.
Carl Djerassi was one of Julian’s many rivals in the competition to synthesize cortisone, and he eventually followed Marker at Syntex. Djerassi came to the United States in 1939, after fleeing the Nazis in Austria. He began his higher education at Tarkio College in Missouri and then transferred to Kenyon College in Ohio. Upon receiving his bachelor’s degree in chemistry, he spent a brief period working on antihistamines for the Swiss pharmaceutical company CIBA at its New Jersey facility. He completed a doctorate in organic chemistry at the University of Wisconsin, where he wrote his dissertation on how to transform the male sex hormone testosterone into the female sex hormone estradiol, using a series of chemical reactions. Djerassi’s longtime fascination with steroids prompted his return to CIBA, but he was not allowed to work on steroid synthesis there. That promising field of research was reserved for the laboratories at CIBA’s corporate headquarters in Switzerland. Djerassi was disappointed, and in 1949—shortly after Julian’s paper on Substance S appeared—he joined Syntex in Mexico City.
Syntex was trying to synthesize cortisone from diosgenin, having already produced male and female sex hormones from diosgenin under Marker’s initiative. In 1951 Djerassi’s group successfully synthesized cortisone, improving on a procedure originally developed in 1944 by Merck and Company. The Syntex process not only used a cheaper raw material but also required only about half as many steps. Soon other groups reported their syntheses. In the end the Upjohn Company was most successful commercially, with its use of a microorganism to convert progesterone to cortisone, but Syntex benefited, too, because it was commissioned to supply the progesterone to Upjohn.
In 1951, the same year that Djerassi’s group at Syntex synthesized cortisone, it also synthesized the first effective oral contraceptive. It had long been known that during pregnancy progesterone serves as a natural contraceptive by inhibiting further ovulation while maintaining the proper uterine conditions for the fetus. But taking natural progesterone orally weakens its biological activity, and thus the search was on for a more active sex hormone that could survive digestive processes. A compound synthesized at Syntex proved to be one of the most potent oral progestins ever made. The U.S. Food and Drug Administration approved Syntex’s norethindrone as well as a related drug synthesized at G. D. Searle and Company, first as a treatment for menstrual difficulties (1957) and then as an oral contraceptive (1960). Searle’s norethynodrel differed from norethindrone in the location of just one double bond in the molecule.
Djerassi maintained a 20-year relationship with Syntex, while also accepting academic appointments after his 1951 triumphs, first at Wayne State University in Detroit and then at Stanford University. He made many more advances in synthetic organic chemistry and refined the techniques of mass spectroscopy and methods for deducing the precise orientation in space of the atoms in a molecule from optical rotatory dispersion.
Djerassi is a social activist as well as a scientist. In line with his work on the birth-control pill, he seeks to raise consciousness about the global need for population control. Stemming from his years with Syntex have been his efforts to encourage science in developing countries like Mexico. In memory of his daughter, who was an artist, and consonant with his own artistic and literary interests, he has established a colony for artists near Santa Cruz, California.