Percy Lavon Julian

Percy Lavon Julian (April 11, 1899 – April 19, 1975) was an American research chemist and a pioneer in the chemical synthesis of medicinal drugs from plants. He was the first to synthesize the natural product physostigmine; and was an American pioneer in the industrial large-scale chemical synthesis of the human hormones, steroids, progesterone, and testosterone, from plant sterols such as stigmasterol and sitosterol. His work would lay the foundation for the steroid drug industry's production of cortisone, other corticosteroids, and birth control pills. He later started his own company synthesizing steroid intermediates from the Mexican wild yam. His work helped reduce the cost of steroid intermediates to large multinational pharmaceutical companies.^[1]

During his lifetime he received more than 130 chemical patents. Julian was the second African American to receive a doctorate in chemistry. He was the first African American chemist inducted into the National Academy of Sciences, and the second African American scientist inducted from any field.^[1]

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Early life and education

Julian was born in Montgomery, Alabama to Elizabeth (1878-?) and James Sumner Julian I (1871–?). James was a railway mail carrier for the United States Post Office, and his father was a slave.^[2][3][4] Elizabeth worked as a school teacher. He grew up in the time of Jim Crow. Among his childhood memories was finding a lynched man hung from a tree while walking in the woods near his home. While it was generally unheard of for African Americans at the time to pursue an education beyond the 8^th grade, Julian's father steered all of his children towards higher education. Julian attended DePauw University in Greencastle, Indiana. At the time, the college accepted very few African American students and the town was segregated. Julian was not allowed to live in the college dormitories and initially stayed in an off campus boarding home where he was refused meals. It was days after his arrival before Julian found an establishment that would allow him to eat. Ultimately, he took work firing the furnace and doing other odd jobs in a fraternity house and, in return for his service, he was allowed to sleep in the basement and eat. He graduated from DePauw in 1920 Phi Beta Kappa and valedictorian.^[5] By 1930 Julian's father had moved the entire family to Greencastle, Indiana so that all his children could attend college at DePauw, he was still working as a railroad postal clerk.^[2]

Julian wanted to obtain his doctorate in chemistry but learned it would be difficult for an African American. He was denied access to American doctorate programs because they felt that the only jobs obtainable post-graduation would be as instructors at all black colleges. After graduating from DePauw, Julian became a chemistry instructor at Fisk University. He then received an Austin Fellowship in Chemistry and went to Harvard University in 1923 for his M.S. Worried that white students would resent being taught by an African American, Harvard withdrew Julian's teaching assistantship and he was unable to complete his Ph.D. at Harvard. In 1929 Julian received a Rockefeller Foundation fellowship to continue his graduate work at the University of Vienna, and he received his Ph.D. in 1931. He studied under Ernst Späth and was considered an impressive student. In Europe, he found freedom from the racial prejudices that nearly stifled him in the States. He freely participated in intellectual social gatherings, went to the opera and found greater acceptance among his peers.^[6][7] Julian was the third African American to receive a Ph.D. in chemistry after St. Elmo Brady and Edward M. A. Chandler.^[1][8]

Physostigmine

After returning from Vienna, he went to Howard University for one year, where met his future wife, Anna Roselle Johnson (Ph.D. in Sociology, 1937, University of Pennsylvania). They married on December 24, 1935 and had two children: Percy Lavon Julian, Jr. (1940- ), a lawyer in Madison, Wisconsin; and Faith Roselle Julian (1944- ).^[5]At Howard, Julian got involved in university politics, he goaded a white chemist named Jacob Shohan into resigning. Shohan retaliated by releasing to the local African American newspaper the letters Julian had written to him from Vienna. The letters contained accounts of his sex life, and criticism of individual Howard faculty members. Julian's laboratory assistant, Robert Thompson, also charged he had found his wife and Julian together in a sexual tryst. When Thompson was fired for filing a lawsuit against the University, he released the letters that Julian had written to him from Vienna just as Shohan had. Through the summer of 1932, the Baltimore Afro-American published all of Julian's letters.^[1]

William Blanchard then offered him a position to teach organic chemistry at DePauw University in 1932. Julian helped Josef Pikl, a fellow student at the University of Vienna, to come to the United States to work with him at Depauw. In 1935 Julian and Pikl completed the total synthesis of physostigmine, and confirmed the structural formula assigned to it. Robert Robinson of Oxford University was the first to publish a synthesis of physostigmine, but Julian noticed that the melting point was wrong for Robinson's end product. When Julian completed his synthesis, the melting point matched the correct one for natural physostigmine from the calabar bean.^[1]

Julian also extracted stigmasterol, which took its name from Physostigma venenosum, the west African calabar bean that he hoped could serve as raw material for synthesis of human steroidal hormones. At about this time, 1934, Butenandt ,^[9] and Fernholz ^[10] ,in Germany, had shown that stigmasterol, isolated from soybean oil, could be converted to progesterone by synthetic organic chemistry. I.G. Farbenindustrie up to 1945 was manufacturing about 5 kilograms per year of progesterone by this method. ^[11]

Glidden

After being denied a professorship at DePauw in 1936 for racial reasons, Julian applied for a job at the Institute of Paper Chemistry (IPC) in Wisconsin. However, the Wisconsin city of Appleton where the institute was located, was a sundown town, forbidding African Americans from staying overnight. DuPont had offered a job to fellow chemist Josef Pikl, but declined to hire Julian, who had superlative qualifications as an organic chemist, apologizing that they were "unaware he was a Negro".^[1]

Julian wrote to the Glidden Company, a supplier of soybean oil products, to request a 5-gallon sample of the oil to use as his starting point for the synthesis of human steroidal sex hormones. After receiving the request, W.J. O'Brien, a vice-president at Glidden made a telephone call to Julian, offering him the position of director of research of Glidden's Soya Products Division in Chicago. He was very likely offered the job by O'Brien because he was fluent in German and Glidden had just purchased a modern continuous countercurrent solvent extraction plant from Germany for the extraction of vegetable oil from soybeans for paints and other uses.^[1]

Julian supervised the assembly of the plant at Glidden when he arrived in 1936. He then designed and supervised construction of the world's first plant for the production of industrial-grade, isolated soy protein from oil-free soybean meal. Isolated soy protein could replace the more expensive milk casein in industrial applications such as coating and sizing of paper, and in the manufacture of water-based paints. Just prior to World War II, Julian discovered that upon hydrolysis, soy protein could be used as a fire-extinguisher when converted into a foam by means of an aerating nozzle. It could smother oil and gasoline fires on board ships, before the flames could engulf the ship. This invention saved the lives of thousands of American sailors.^[1] Citing this, in 1947 the NAACP awarded him the Spingarn Medal, its highest honour.^[12]

Steroids

  Julian's research at Glidden changed in 1940 when he began work on synthesizing progesterone, estrogen and testosterone from the plant sterol stigmasterol, and sitosterol isolated from soybean oil by a foam technique he invented. At that time clinicians were discovering many uses for the newly discovered sex hormones. However, only minute quantities could be produced from the extraction of hundreds of pounds of spinal cords, testicles or ovaries. In 1940 Julian produced 100 lb of mixed soy sterols daily and the value of this daily by-product in terms of sex hormones was $10,000 daily. Julian was soon ozonizing 100 pounds daily of mixed sterol dibromides. The result was the female hormone progesterone which was put on the American market in bulk for the first time and other sex hormones soon followed. ^[13]

His work made possible the production of these hormones on a larger (kilogram) industrial scale, with a potential of reducing the cost of treating hormonal deficiencies. Julian and his co-workers obtained patents for Glidden on key processes for the preparation of progesterone and testosterone from soybean plant sterols, but product patents held by a former cartel of European pharmaceutical companies prevented a significant reduction in wholesale and retail prices for clinical use of these hormones in the 1940s.^[14][15][16]

On April 13, 1949, rheumatologist Philip Hench at the Mayo Clinic announced the dramatic effectiveness of cortisone in treating rheumatoid arthritis. The cortisone was produced by Merck at great expense using a complex 36-step synthesis developed by chemist Lewis Sarett starting with deoxycholic acid from cattle bile acids. On September 30, 1949, Julian announced an improvement in the process of producing cortisone from bile acids that eliminated the need to use osmium tetroxide (a rare and expensive chemical), and said, further, that by 1950, Glidden would begin producing closely related compounds which may have partial, cortisone, activity. Julian also announced the synthesis, starting with pregnenolone from soybean oil sterols of the steroid cortexolone and possibly 17α-hydroxyprogesterone and pregnenetriolone, which he hoped might also be effective in treating rheumatoid arthritis ^[17].^[18]

On April 5, 1952, biochemist Durey Peterson and microbiologist Herbert Murray at Upjohn published the first report of a fermentation process for the microbial 11α-oxygenation of steroids in a single step (by common molds of the order Mucorales). Their fermentation process could produce 11α-hydroxyprogesterone or 11α-hydroxycortisone from progesterone or Compound S, respectively, which could then by further chemical steps be converted to cortisone or 11β-hydroxycortisone (cortisol).^[19] After two years, Glidden abandoned production of cortisone from bile acids to concentrate on Compound S. Julian developed an excellent multistep process for conversion of pregnenolone, available in abundance from soybean oil sterols to cortexolone. In 1952, Glidden, which had been producing progesterone and other steroids from soybean oil, shut down its own production and began importing them from Mexico through an arrangement with Diosynth (a small Mexican company founded in 1947 by Russell Marker after leaving Syntex). Glidden's cost of production of cortexolone was relatively high, so Upjohn decided to use progesterone, available in large quantity at low cost from Syntex, to produce cortisone and hydrocortisone.^[20]

In 1953, Glidden decided to leave the steroid business which had been relatively unprofitable over the years despite Julian's innovative work.^[21] On December 1, 1953, Julian left Glidden after 18 years, giving up a salary of nearly $50,000 a year, to found his own company, Julian Laboratories, Inc., taking over the small, concrete-block building of Suburban Chemical Company in Franklin Park, Illinois.^[22][23]

On December 2, 1953, Pfizer and Syntex acquired exclusive licenses of Glidden patents for the synthesis of Compound S. Pfizer had developed a fermentation process for microbial 11β-oxygenation of steroids in a single step that could convert Compound S directly to 11β-hydrocortisone (cortisol), with Syntex undertaking large-scale production of cortexolone at very low cost.^[20]

Oak Park

Around 1950 Julian moved his family from Chicago to the suburb of Oak Park, Illinois, where the Julians were the first African American family.^[24] Although some residents welcomed them into the community, there was also widespread antipathy towards them. Their home was fire-bombed on Thanksgiving Day, 1950, before they moved in. After they moved to Oak Park, the house was attacked with dynamite on June 12, 1951. The attacks galvanized the community and a community group was formed to support the Julians.^[25] Julian's son later recounted that during these times, he and his father often kept watch over the family's property by sitting in a tree with a shotgun.^[1]

In 1953, he founded his own research firm, Julian Laboratories, Inc. He brought many of his best chemists including African Americans and women from Glidden to his own company. He won a contract to provide Upjohn with $2 million worth of progesterone. To compete against Syntex he would have to use the same Mexican yam as his starting material. He borrowed and used his own money to build a processing plant in Mexico, but could not get a permit to harvest the yams from the government. Abraham Zlotnik found a new source of the yam in Guatemala for the company.

In July 1956, Julian and executives of two other American companies trying to enter the Mexican steroid intermediates market appeared before a U.S. Senate subcommittee and testified that Syntex was using undue influence to monopolize access to the Mexican yam.^[16][26] The hearings resulted in Syntex signing a consent decree with the U.S. Justice Department in which it did not admit to restraining trade but promised not to do so in the future.^[16] With the doors to the Mexican steroid intermediates market forced open by the U.S. government, within five years, large American multinational pharmaceutical companies had acquired all six producers of steroid intermediates in Mexico (four of which had previously been Mexican-owned).^[16]

Syntex had reduced the cost of bulk progesterone as an intermediate more than 250-fold over twelve years, from $80 per gram in 1943 to $0.31 per gram in 1955.^[16][26] Competition from Upjohn and General Mills, who had together made very substantial improvements in the production of progesterone from stigmasterol, forced the price of Mexican progesterone down to less than $0.15 per gram in 1957, and the price continued to fall, bottoming out at $0.08 per gram in 1968.^[20][16] In 1958, Upjohn purchased 6,900 kg of progesterone from Syntex at $.135 per gram, 6,201 kg of progesterone from Searle (who had acquired Pesa) at $0.143 per gram, 5,150 kg of progesterone from Julian Laboratories at $0.14 per gram, and 1,925 kg of progesterone from General Mills (who had acquired Protex) at $0.142 per gram.^[27]

Despite continually falling bulk prices of steroid intermediates, an oligopoly of large American multinational pharmaceutical companies kept the wholesale prices of corticosteroid drugs fixed and unchanged year after year into the 1960s (cortisone fixed at $5.48 per gram from 1954, hydrocortisone fixed at $7.99 per gram from 1954, prednisone fixed at $35.80 per gram from 1956).^[16][27] Merck and Roussel Uclaf concentrated on improving the production of corticosteroids from cattle bile acids—in 1960 Roussel produced almost one-third of the world's corticosteroids from bile acids.^[20]

One year Julian Laboratories chemists found a way to quadruple the yield on a product on which they were barely breaking even, and Julian reduced their price for the product from $4,000 per kg down to $400 per kg.^[1]

He sold the company in 1961, for $2.3 million dollars.^[28] The U.S. and Mexico facilities were purchased by Smith Kline and his chemical plant in Guatemala was purchased by Upjohn. In 1964, he founded Julian Associates and Julian Research Institute, which he managed for the rest of his life.^[29]

National Academy of Sciences

He was elected to the National Academy of Sciences in 1973 in recognition of his scientific achievements. He was the second African American after David Blackwell.

Death

Julian died of liver cancer on April 19, 1975 in St. Theresa's Hospital in Waukegan, Illinois and was buried in Elm Lawn Cemetery in Elmhurst, Illinois.^[30][3][31]

Legacy

• Received the Chicagoan of the Year award from the Chicago Sun-Times in 1950. ^[5]
• He was honored on a stamp issued by the United States Postal Service in 1993.^[32]
• In 1975, Percy L. Julian High School was opened on the south side of Chicago, Illinois as a Chicago Public High School. In 1983, Hawthorne School in Oak Park was renamed Percy Julian Middle School. In 1980, the science and mathematics building on the DePauw University campus was rededicated as the Percy L. Julian Mathematics and Science Center; in Greencastle, Indiana, where DePauw is located, a street was named after him, as well as Julian Hall at Illinois State University, where he was on the board of trustees.^[33]
• In 1999, the American Chemical Society recognized Julian's synthesis of physostigmine as one of the top 25 achievements in the history of American chemistry.^[34]

Archive

The Percy Lavon Julian family papers are archived at DePauw University. ^[35]

Patents

• U.S. Patent 2,373,686 ; Jul 15, 1942; Phosphatide Product And Method Of Making
• U.S. Patent 3,761,469 ; September 25, 1973; Process For The Manufacture Of Steroid Chlorohydrins; with Arnold Lippert Hirsch

Publications

• Studies in the Indole Series. I. The Synthesis of Alpha-Benzylindoles; Percy L. Julian, Josef Pikl; J. Am. Chem. Soc. 1933, 55(5), pp 2105-2110.
• Studies in the Indole Series. V. The Complete Synthesis of Physostigmine (Eserine); Percy L. Julian, Josef Pikl; J. Am. Chem. Soc. 1935, 57(4), pp 755-757.

References and notes