History of Medicine

     The noted science historian, Steven Shapin, recently related a story about a cardiac surgeon who, on retiring, decided to take up medical history. He approached a medical historian to ask her for a few pointers. She replied that she was also about to retire and was thinking of taking up cardiac surgery. She asked if in return for her pointers on medical history she could receive some on cardiac surgery. (Wall Street Journal Book Review, Feb 14-15, 2015).

Letting you know that I am a retired physician, here is the next blog!

CARL DJERASSI

     Carl Djerassi died in late January, and it seems fitting to reflect on his life and influence. He is often called the father of “the pill”, and though that is an exaggeration his career has been remarkable. He was, in my judgement, one of that disappearing species known as “Renaissance Man”.

     Briefly, he was born in Vienna in 1923. His father was Bulgarian and his mother Austrian, both physicians. They divorced when he was 6 but did not tell him, remarried at the time of the Anschluss to get necessary papers to transport him to America (with his mother), and re-divorced. After appealing to Eleanor Roosevelt by mail he obtained a scholarship, finishing college at Kenyon College, Ohio, at the early age of 19. Then on to a job at CIBA for 4 years, where the lab he worked in synthesized pyribenzamine, the first antihistamine. He took a break from CIBA for a PhD at U of Wisconsin in steroid chemistry and after returning to CIBA he became restless and accepted a research position at a small, lesser-known company in Mexico City, Syntex. Why Syntex? Djerassi admits that he wanted to enter academia, but for a chemist coming from industry in the 1940s this was unrealistic. Syntex had grown by synthesizing progesterone and testosterone from diosgenin, a component of Mexican yams, and marketing it in bulk. The director of research at Syntex, George Rosenkrantz, knowing Djerassi’s strength in steroid chemistry, offered him modern equipment, a relatively free hand, and rapid publication of his work, the latter allowing him to establish a reputation. And, he admits, he was something of a gambler. The idea of a foreign country and a new language appealed to him, still in his twenties.

     When Djerassi arrived the race was on for a way to synthesize cortisone, recently shown to benefit arthritics but costing nearly $200/gram, and laboriously made from animal bile through 36 chemical steps. Although his group succeeded in synthesizing cortisone, scientists at Upjohn grabbed the market with a more economical method using microbial fermentation of progesterone. Djerassi, along with George Rosenkranz and Luis Miramontes (chemistry student), next synthesized norethindrone, the first oral progesterone-like inhibitor of ovulation. Soon after, Frank Colton at Searle synthesized norethynodrel, a closely related molecule (actually a product of norethindrone treated with acid, even stomach acid). The pill was born.

     Djerassi, still seeking an academic connection, accepted a tenure-track position at Wayne University (later Wayne State U) in 1952. There he turned from synthesis to structure elucidation and studied sterol components of cacti, coffee, and other plant sources. He utilized mainly physical methods to determine structure, inventing one himself. Then came a call from Stanford, where he went in 1960 with an old professor of his from the U of Wisconin, William S. Johnson, and where a blend of academic and commercial work was encouraged (he still had an important position at Syntex). He continued work on sterols, including marine sterols, was pioneering in the use of physical methods for structure elucidation, founded a company (Zoecon) to use pheromones as possible insecticide agents, taught a class in biosocial aspects of birth control, and was active in Pugwash Conferences.  He received many honorary degrees and numerous awards, one of which was the National Medal of Science, which Nixon bestowed on him at a time that he was on Nixon’s list of enemies. There is even a glacier in Antarctica named after him. It is not far from Paré Glacier, Malpighi Glacier, and Pirogov Glacier. A little farther away is Mount Rokitansky. (If anyone knows why these medical names were chosen for Antarctica, please tell me.)

     Tragedy struck when his daughter, an artist, committed suicide, after which he established a residence for artists on land he had purchased for a cattle ranch. This matured into a large artist colony. Djerassi, in his later years, took to writing fiction, memoirs, and plays, and established a large collection of works by Paul Klee. He characterizes his fiction as “science-in-fiction”, with two goals: to convey scientific information in a user-friendly manner, and to depict “how the game is played” in science – competition, academic tenure, priorities, journal choices, etc. His first novel, Cantor’s Dilemma, was well received and became assigned reading in some college courses. Newton’s Darkness, a play I enjoyed in San Francisco, was about the debates between Newton and Leibniz and Hooke.

     He gave much thought to issues of birth control and population control, laid out in some of his books and articles.

     What was the background to Djerassi’s synthesis of norethindrone? Djerassi himself starts the story with an experiment performed by Ludwig Haberlandt (1885-1932) in 1919. Haberlandt was a physiology professor at the University of Innsbruck when he transplanted the ovaries of a pregnant rabbit under the skin of a non-pregnant rabbit and showed inhibition of pregnancy for about 2 ½ months in spite of frequent coitus. Veterinarians had known for some time that manually pushing out a persistent corpus luteum cyst (apparently common in brucellosis) would restart the ovulation cycle and allow pregnancy in cows. The corpus luteum was known since its description in 1672 by Regner de Graaf, but its function remained obscure. In 1898 Auguste Prenant, professor of histology at Nancy, postulated that the c luteum had endocrine functions, including the possibility of inhibiting ovulation during pregnancy (an idea put forth a little earlier by John Beard, an anatomist at the Univ of Edinburgh). In the early 1900s Jacques Loeb and colleagues noted that corpus lutea would suppress ovulation, and if removed ovulation would resume.

     With this background Haberlandt did his experiments and published widely. He even achieved temporary sterility in mice by an oral route using ovarian and placental extracts. He seems to have been the first to talk of “temporary sterilization” and “hormonal sterilization”, seeing it as useful in determining family size and as an aid in eugenics. He is the first to use the term birth control (“Geburtenregelung” in: Monatsschrift für Geburtshülfe und Gynäkologie 1931, 87:320-332). He quoted Freud in thinking of hormonal sterilization as a way to free the satisfaction of natural desire from the act of procreation, but the medical community showed little interest (see Simmer, below). He collaborated with a Hungarian pharmaceutical company to produce an oral preparation for human use, called “Infecundin”, but it is unclear if it was ever marketed (Haberlandt died shortly after).

      Others confirmed Haberlandt’s experiments. In 1928 George Corner and William Allen achieved an extraction from corpus lutea of a material they called “progestin”. Five years later Allen and Oscar Wintersteiner, coincidentally with Adolf Butenandt (later nobel laureate) and Ulrich Westphal, achieved the crystalline isolation of pure material. In 1935, at a pre-conference party in London a conversation was held over drinks to give it a name. Allen and Corner suggested “Progestin”, while Butenandt proposed “Luteosterone”. They compromised on “Progesterone”.

     But progesterone was expensive, $80/gram in the early 1940s, and Butenandt had used corpus lutea from 50,000 pigs to make a few grams (Medvei,p 402). The breakthrough came from an unusual, some say “maverick”, chemist, Russell Marker. Marker had left his PhD program at the U of Maryland abruptly, without a degree, and as a research chemist at Pennsylvania State College worked on plant sterols, called sapogenins, especially diosgenin, found abundantly in inedible Mexican yams. He invented a simple five-sep conversion of diosgenin into progesterone, and using his savings went to Mexico, where the yams were, set up a primitive lab, and made about 3 kilos of progesterone. He then approached a small laboratory that he found in a Mexican phone book, Laboratorios Hormona, about a collaboration. The new company was renamed Syntex. This worked for about a year, then Marker left abruptly and a short time later left chemistry altogether. Syntex recruited George Rosenkrantz, a Hungarian working in Cuba, to run research, and it was he who recruited Djerassi.

     Next time: The Pill “goes public”.

The above scribblings are obtained primarily from:

Djerassi, C: The Pill, Pygmy Chimps, and Degas’ Horse. 1992

Djerassi, C: This Man’s Pill. 2001.

Medvei, VC: A History of Endocrinology. 1982

Simmer, HH: On the History of Hormonal Contraception. I. Ludwig Haberlandt and his Concept of “Hormonal Sterilization”. Contraception 1970. 1: 3-27.