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."
