ACS NEWS
Volume 77, Number 43
CENEAR 77 43 pp.
ISSN 0009-2347
C&EN Washington
" There are more stories told about Russell Marker than perhaps any other 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." --Steven M. Weinreb, Russell & Mildred Marker Professor of Natural Products Chemistry, Pennsylvania State University
On Oct. 1, representatives of the Mexican and U.S. chemical communities, along with 15 high-school and college chemistry students from the American Chemical Society Central Pennsylvania Section, gathered under crisp blue skies in University Park, Pa., to tell the story of Russell Marker (1902-95) and to designate the Marker degradation and the creation of the Mexican steroid hormone industry as an International Historic Chemical Landmark. The designation was conferred jointly by ACS and the Sociedad Química de México (SQM). Similar observances are scheduled this week in Monterrey, Mexico, and a final ceremony will be held Dec. 2 in Mexico City.
From left: Noriega Bernechea, James Marker, Wasserman, and Larson [Photo by Linda Raber]
A plaque was unveiled by ACS President Ed Wasserman and SQM President-elect Jaime Noriega Bernechea just outside Pond Laboratory on the Pennsylvania State University campus, where Marker achieved the first practical synthesis of progesterone. This synthesis led to the creation, in Mexico, of Syntex S.A., and a number of competing companies, and made Mexico an important contender in the steroid pharmaceutical industry.
The inscription on the plaque reads: "In Pond Laboratory, Russell E. Marker achieved the first practical synthesis of the pregnancy hormone, progesterone, by what now is known as the 'Marker degradation.' After discovering an economical source of his starting material in a species of Mexican yam, Marker commercialized his process in 1944 at Syntex, which he founded in Mexico City with Emeric Somlo and Federico A. Lehmann.
"This low-cost progesterone eventually became the preferred precursor in the industrial preparation of the anti-inflammatory drug cortisone. In 1951, Syntex researchers synthesized the first useful oral contraceptive from Marker's starting material. Syntex and its competitors in Mexico thus became a powerful international force in the development of steroidal pharmaceuticals."
Speakers at the festivities included Wasserman and Noriega Bernechea along with Weinreb; Daniel J. Larson, dean of the Eberly College of Science at Penn State; Paul F. de Cusati, former chair of the ACS Central Pennsylvania Section; and Andrew G. Ewing, chairman of Penn State's chemistry department. Marker's son James and his wife, their daughters, and Marker's grandson by his son Russell attended.
ACS has been designating historic chemical landmarks since 1993. And three other landmarks have honored international achievements this year (C&EN, Jan. 18, page 103; May 10, page 40; June 28, page 74). "The purpose of the landmarks program is to remind the chemistry community of its rich heritage and to encourage the public's appreciation of the vital role that chemistry has played in our nation's--indeed the world's--history," Wasserman said. "This year, as part of the International Chemistry Celebration, we join with our sister scientific societies to emphasize international landmarks to underscore the principle that scientific research and discovery know no national boundaries," he said.
Marker was directly responsible for bringing important medicines within the reach of ordinary people. But the road to this goal wasn't well traveled, and it involved perseverance, some surprising twists and turns, and Marker's very unusual personality.
Marker, who was born on his father's farm near Hagerstown, Md., in 1902, received a bachelor's degree from the University of Maryland in 1923 and a master's degree in physical chemistry in 1924. He then started doctoral research with Morris Kharasch at Maryland. Within a year, Marker had completed enough work for his thesis but still needed to take some physical chemistry courses.
But it wasn't to be. Marker considered physical chemistry classes a waste of time and refused to take them. Kharasch warned that Marker would endup a "urine analyst" if he didn't complete the requirements. Marker accepted this challenge and left the university in 1925. After several years of working at Ethyl Corp., where he invented the gasoline "octane number" rating system, Marker figured he had enough hydrocarbon experience, so he began research with P. A. Levene at Rockefeller Institute. Over the next six years, Marker published 32 papers on optical rotation and molecular configuration. Then he decided to change his focus to steroid research and began work at Pennsylvania State College in a position funded by Parke-Davis.
The time was right. Sex hormones had been introduced into medical practice as drugs in the 1930s. One of these, progesterone, the so-called pregnancy hormone, is responsible for maintaining the proper uterine environment for a developing fetus. Progesterone also inhibits ovulation, preventing another pregnancy from occurring while a woman is pregnant.
Medically, progesterone was of particular interest because it was valuable in treating certain menstrual disorders as well as in preventing some types of miscarriages. At the research level, it was thought to be potentially useful in treating cervical cancer, although that didn't pan out. Whatever its benefit, its cost severely restricted its use.
[Photo by Juan Guzmán]
Progesterone was expensive because it was maddeningly difficult to make in any quantity. Virtually all of the progesterone that was used for clinical purposes in those days was prepared from cholesterol through three of its oxidation products. These reactions were inefficient and resulted in a low supply of the hormone and very high prices.
In 1938, Marker proposed a new molecular structure for sarsasapogenin, a plant steroid isolated from sarsaparilla. In Marker's proposed structure, the side chain of the molecule is chemically reactive. Earlier researchers had believed that the side chain was chemically inert. On the basis of his hypothesis, Marker invented a chemical reaction sequence that removed most of the atoms in the side chain. What remained duplicated the side chain of progesterone. This kind of reaction is called a degradation. A bit of chemical modification of the steroid ring system yielded progesterone.
But sarsasapogenin was also extraordinarily expensive, so Marker began a search for a plant steroid of the sapogenin class, starting in the southwestern U.S. and ending in Mexico. In November 1941, while paging through a botany text, he saw a promising picture of dioscorea, a type of wild yam that grew in the Mexican state of Veracruz near Orizaba.
Marker went to Mexico, collected two big roots of dioscorea, loaded them into bags, and put them on the top of a bus. When he got to Orizaba, the bags were gone, but he recovered the larger, 50-lb root by bribing a policeman. The tuber, which he ended up smuggling out of the country, yielded a good quantity of diosgenin--a convenient and cheap starting material that he believed could yield progesterone by the ton. Marker's discovery was about to change progesterone from a costly rarity to the cheapest of all steroid hormones. But he had a hard time persuading anyone to invest in his idea.
In a 1979 interview with Stanford University chemist Carl Djerassi, another pioneer of the Mexican steroid hormone industry, Marker recalled how he could not convince Parke-Davis to support the commercialization of his synthesis. "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," Marker said during the interview, recorded in Djerassi's book "From the Lab into the World."
So Marker withdrew all of his savings from the bank, went down to Veracruz, and collected 9 or 10 tons of the roots. And, Marker told Djerassi, at a "coffee drying place" right across the street from where he collected the material, the roots were sliced like potato chips and dried in the sun. He then took the chips to Mexico City and had them ground up. He extracted the root with alcohol and evaporated it down to a syrup that he took back to the U.S. Marker made 3 kg of the hormone, the largest lot that had ever been produced; progesterone was then selling at $80 per g.
Marker hoped he would have more success in getting entrepreneurs in Mexico interested in his process, so, while there, he looked up "Laboratorios" in the phone book and found Laboratorios Hormona. That sounded promising, so he pitched his process to the lab. The lab's owner was Somolo, a Hungarian businessman with a doctorate in law who had immigrated to Mexico in 1928 to start a drug import business. In 1933, Somolo had brought Lehmann, a medical doctor with a Ph.D. degree, from Germany and started Laboratorios Hormona in anticipation that it would soon be difficult to obtain drugs from Europe. The deal they cut with Marker started Syntex in 1944. By then, Marker had ended his research program at Penn State.
It was not a marriage made in heaven. In May 1945, Marker and his partners got into an acrimonious dispute over profits and their distribution. Marker severed all ties with Syntex and left the company. Syntex wasn't able to make any more progesterone immeditately because Marker had done all of the key operations himself, had coded the reagent bottles, and had left no directions.
Marker then started making progesterone in Mexico City at his new company--Botanica-mex, which was soon sold to Gedeon Richter Ltd. Gedeon Richter started production in Mexico City under the name Hormonosynth. After Marker retired, the company was reorganized as Diosynth.
But Syntex did not fade into the background, and that's the second half of the story. The company hired George Rosenkranz, who had studied at the Swiss Federal Institute of Technology and was conducting pharmaceutical research in Cuba. Syntex was back up and running in a few months. Rosenkranz is responsible for building a powerful research program at Syntex; in part this was done by playing a major role in the creation of the Instituto de Química, where a collaborative organic chemistry research degree was established. Rosenkranz also recruited other Ph.D. chemists, including Djerassi and biotechnology entrepreneur Alejandro Zaffaroni.
One particular research program led by Djerassi focused on the conversion of diosgenin to cortisone, which had recently found therapeutic use in treating rheumatoid arthritis. At the time, cortisone could only be made by a 36-step Merck & Co. process that started with desoxycholic acid, which was isolated from ox bile. Almost simultaneously, in 1951, scientists at Upjohn Co. introduced a microbiological process that oxidized progesterone to a compound that was easily converted to cortisone. Soon much of the world's cortisone was manufactured by Upjohn's process that used Syntex progesterone.
Then Syntex began competing with other drug companies in the hunt for an effective oral contraceptive. Because progesterone prevents ovulation, research focused on the discovery of a progesterone mimic that is, unlike progesterone, orally active. In 1951, Djerassi's group designed and synthesized norethindrone, the active ingredient in the first birth control pill. By the 1950s, Syntex and its competitors in Mexico were producing more than half of the sex hormones sold in the U.S. In 1951, Fortune magazine headlined an article: "Syntex makes the biggest technological boom ever heard south of the border."
Noriega Bernechea said the "debt of gratitude that
Mexican research and education owe Syntex cannot be
overshadowed by anything." The foremost research facility in
Mexico, he explained, is the Instituto de Química of
the National University, and it "had its biggest push and
fulfillment by the work of people promoting research at
Syntex." Specifically, he said, "Djerassi is still held in
great honor in Mexico--of course, with the knowledge that it
was Marker who started it all."
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