THE PILL GOES PUBLIC

    In March, 1914, a new publication circulated in New York: The Rebel Woman. The front page set a feisty tone:

     “Why the Rebel Woman?

Because I believe that deep down in woman’s nature lies slumbering the spirit of revolt. Because I believe that woman is enslaved by the world machine, by sex conventions, by motherhood and its present necessary child-rearing, by wage slavery, by middle-class morality, by customs, laws, and superstitions. Because I believe that woman’s freedom depends upon awakening that spirit of revolt within her against these things that enslave her…”

     This was the opening salvo by the most ardent promoter of birth control in the U.S., Margaret Sanger. She was one of 11 children whose mother survived 18 pregnancies only to perish soon after from tuberculosis. Margaret attended nursing school but married an architect before finishing. The couple migrated to New York City where Margaret gravitated to Greenwich Village and was introduced to labor activism, socialism, and women’s movements. At the same time she worked as a visiting nurse on the Lower East Side where she confronted poverty-stricken families with large numbers of children, mothers ignorant of contraceptive methods and venereal disease, and deaths from illegal abortions. The result was The Woman Rebel, a blend of demands for contraception, socialism, and labor activism. After a trip to Europe where she met Havelock Ellis, Malthusians, and other social thinkers, and (like Marx) read a good deal in the British Library, she returned with a sharper focus: birth control as a means of easing poverty and allowing women greater independence in their sex lives. Soon she added eugenic benefits to her platform.

Margaret Sanger

     In fact, though, the birth rate in the U.S. had been falling since 1800. By 1900 the average family had just over 3 children and by 1936 the birth rate was a little below the replacement rate. Birth control was being practiced, though quietly and mainly by the middle class. President Teddy Roosevelt even commented on “race suicide”, fearing that the immigrant classes were out-breeding the more “desirable” ones.

     Margaret opened a birth control clinic and published material on contraception, leading her into conflict with the law, namely the Federal Comstock Act. The Act, from 1873, prohibited the mailing of lewd and obscene publications, prints or pictures, contraceptive articles, and advertisements for and information about contraception. The law was so influential that in WWI American soldiers went to Europe without a condom supply, the only Allied troops without such armor. The resultant venereal disease rate was severe (Mil. Med. 1918,42: 568-70). Through the next two decades the Act was weakened through several court cases, often involving the combative Sanger, that broadened the escape clause allowing contraceptive advice and devices “for the health of the mother”. A 1936 Federal Appeals Court case modified this to permit contraceptive advice by “conscientious and competent physicians for the purpose of saving life or promoting the well being of their patients”. Congress, though, did not remove language about contraception from the Act until 1971.

     Where was the medical profession during all this? Far behind, is the answer. Major concerns that held organized medicine back were a lack of studies of efficacy and safety of contraceptive devices, an aversion to alliance with groups that used headline grabbing for effect, a feeling that contraception was associated with abortion, worries about conflict with the law, and often moral distaste for the subject. There were, of course, proponents of birth control, including Abraham Jacobi, the “father” of American Pediatrics. The most influential advocate was Robert L. Dickinson, a prominent gynecologist. In his 1920 presidential address to the Amer. Soc. Ob Gyn he urged the Society to address contraception, pointing out the extreme medical ignorance on the subject and even asking “What, indeed, is normal sex life?” (Am J Ob Gyn 1920,1:6).  He pleaded for studies and information, but little happened. In 1923 he established doctor-staffed clinics in seven New York hospitals to dispense contraceptive advice, but few women showed up, apparently preferring the less threatening Sanger-type clinic. He also sent out questionnaires to New York members probing knowledge of contraception (Am J Ob Gyn 1924, 7:266-7). The AMA noted that their opinions “vary as much as those of laymen” (JAMA 1924, 83: 2020-1). Dickinson then attempted to work with Sanger’s clinic as the only place where proper data could be secured, but the medical establishment would not cooperate unless she relinquished control, which she refused to do.

      In 1932 Leo Latz, a practitioner in Chicago, published “The Rhythm of Fertility and Sterility in Women”, a book citing an 8 day period when intercourse should be avoided, to avoid conception. The advice was based on recently completed studies of ovulation times by Oniga and Krause showing that ovulation occurred between 16 and 12 days from the onset of menses. Latz’s approach became known as the “rhythm method”. But it, too, was imperfect.

      In 1936, after years of no progress, the AMA appointed a new committee to study contraception. The new committee was more accommodating, recognized the widespread use of contraception, and opined that planning the number and spacing of children would contribute to the health and well-being of a family. Prescriptions for such devices should be given under medical supervision, though, and principles of birth control and fertility should be taught in medical schools (JAMA June 26, 1937, p2204). The AMA was finally aboard.

      By the end of WWII contraception in the U.S. was widely accepted. Margaret Sanger’s clinics, now morphed into Planned Parenthood clinics, were common.

     In this setting Margaret Sanger in 1950, now aged 70, approached a biologist, Gregory Pincus, about the possibility of an easy-to-take medicine for birth control, preferably a pill. Pincus, raised in the Woodbine Colony, a kibbutz-like Jewish farming settlement in New Jersey had risen to secure a biology research position at Harvard. His first breakthrough was to fertilize a rabbit egg in vitro and produce offspring. Screaming headlines announced the finding, comparing it to Brave New World and other scenarios. Next he fertilized an egg without sperm, generating more headlines. For reasons never made clear, but perhaps related to the glaring publicity and being Jewish, he was dropped from the Harvard staff, couldn’t find another job, and, with much effort and outside help, started his own research institute, the Worcester Foundation for Experimental Biology. With the help of M.C. Chang, a talented researcher and close companion, the Institute grew.

      At the meeting with Sanger Pincus said yes, he thought a pill was possible.

      To help funding, Sanger enlisted another formidable feminist (and friend), Katharine McKormick. McKormick was one of the first women to graduate from MIT and had married Stanley McKormick, heir to the International Harvester fortune. Tragically, Stanley developed schizophrenia and remained intractably ill the rest of his life. Katherine did not divorce and pursued a number of women’s rights issues, including birth control. Her husband died in 1947, leaving her a fortune, some of which funded the project under Pincus. Planned Parenthood and Searle also contributed.

     Pincus focused on the Searle product, norethynodrel He turned to John Rock, a prominent gynecologist at Harvard, who had been using progesterone to try and induce pregnancy. He was a perfect ally - a respected Harvard physician, interested in contraception, and a Catholic. In his practice he encountered enough women who feared having more children to believe that contraception had a role in women’s health. He agreed to help. Trials on his patients confirmed suppression of ovulation, but larger numbers were needed.

     So Pincus turned to Puerto Rico (and Haiti) where the birth rate was high and the population poor. Studies there confirmed the safety of the pill, that a small amount of estrogen enhanced the effect, and that various menstrual disorders were improved. With these data Searle approached the FDA and received approval of their drug, Enovid, for treatment of amenorrhea, dysmenorrhea, and menorrhagia in 1957. No mention was made of contraception. Further studies in Puerto Rico confirmed its ability to prevent pregnancy and be safe, and FDA approval was obtained for contraception in May, 1960, though limiting its use to two years, allowing further studies to be done. Ortho-Novum, using the Syntex product, came next. The Pill, and the Sixties, were born.

In addition to the above references, works consulted were:

Reed, J. The Birth Control Movement and American Society, 1984.

Kennedy, David. Birth Control in America. 1970

Engelman, Peter. A History of the Birth Control Movement in America. 2011

Eig, Jonathan. The Birth of the Pill. 2012.

Baker, Jean. Margaret Sanger: A Life of Passion. 2011.

    

    

    

    

     

     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.

    

    

    

     

Origins of American Tropical Medicine

     War stimulates medical advances. The surgical treatment of wounds, prevention and treatment of disease, even high altitude and space problems have all benefitted from military considerations. And war created the specialty of tropical diseases in the U.S. 

     In Great Britain tropical medicine as a specialty had gotten off to an earlier start, owing to some 300 years of overseas commercial, military, and colonization activities. Patrick Manson, the "father" of tropical medicine in England, published his important textbook in 1898, after contributing heavily to a similar text 5 years earlier edited by Andrew Davidson (Hygiene and Diseases of Warm Climates, 1893). The London and Liverpool Schools of Tropical Medicine were founded in 1899, putting tropical medicine on a firm academic and research footing.

     In the U.S., by contrast, the term "tropical medicine" was seldom heard until the Spanish-American War, though southern states had wrestled with malaria and yellow fever for some time. A devastating epidemic of yellow fever in 1878, for example, originating in New Orleans and sweeping up the Mississippi as far as Ohio leaving wrecked economies and thousands dead (John H Ellis: Yellow Fever and Public Health in the New South, 1992), generated interest in a national public health system and provoked the first of several committees to study yellow fever.

     By the 1880s the germ theory was well entrenched, and in 1880 Alfonse Laveran discovered the malaria parasite, proposed as an alternative to the marsh bacilli claimed by Klebs and Tommasi-Crudeli as being the cause of malaria.  William Osler, an excellent microscopist, appreciated its importance and published on malarial parasites in 1886, when their significance was still questioned (G C Cook: "William Osler's Fascination with Diseases of Warm Climates", J Med Biog, 1995; 3:20-29). William Councilman, pathologist at Hopkins, and colleagues, wrote groundbreaking papers on cerebral malaria and amebic colitis(Am J Med Sci 1885, 89: 416-29; Johns Hopkins Hosp Rep 1891, 2:395-548). George Sternberg, a military physician and one of the first American experts in microbiology, later to become Surgeon General, wrote an excellent book about malaria and another about yellow fever.

     These were beginnings, but it was the Spanish-American War that impelled research and offered careers in this area. Cuba was the site of the famous experiments of the Yellow Fever Commission led by Walter Reed that delineated the mosquito transmission of yellow fever, allowing the construction of the Panama Canal. It was the Philippines, though, where the war against the Spanish had merged into war against Philippine guerrillas, keeping troops there for years, allowing longer-term research - and career opportunities. Very early in the war the Army established laboratories in the Philippines, mainly for diagnostic purposes, and a Research Board. The original order, from S.Gen. Sternberg, included the phrase, "Special attention shall be given to tropical dysentery, to the malarial fevers prevailing in the Philippines, to beriberi, to intestinal parasites, and, in general, to all tropical diseases, the etiology of which has not been worked out." (Army Med Bull. 1929. "A Synopsis of the Army Medical Research Boards in the Philippines". Much of what follows is found there, as are references to all the original papers)

     The principle hospital laboratory was at the First Reserve Hospital in Manila. The first director died of typhoid fever shortly after arrival, and was succeeded by Richard Strong. Strong was a graduate of the first class at the new Hopkins Medical School, and deliberately enlisted so as to be able to work with tropical diseases, citing Osler, Welch and others as creating his interest in this area. He was also assigned to head the Army Research Bureau. He too was incapacitated by typhoid the year after he arrived, but managed to resume work. The Research Board was disbanded in Jan. 1902, and Strong transferred to the newly organized laboratory of the Philippine Government, which soon became the Biological Laboratories of the Philippine Bureau of Science. 

Philippine Bureau of Science

     As a measure of the disease toll on troops, in the first ten months the First Reserve Hospital had 21,955 admissions, only 1,874 of which were for wounds and injuries. 21% of the rest were cases of dysentery and diarrhea, dysentery (2/3 were amebic) accounting for the highest mortality. Malaria, typhoid, brucellosis, dengue fever, and tropical ulcer were prevalent. In the general population smallpox was endemic, as were leprosy, beriberi, tuberculosis, yaws and other skin ailments, and soon cholera and plague made their entrance(Science 1900, V11 ns,p521-28). Many "fevers" were undiagnosed, the only tests that were helpful being malaria smears, Widal tests, blood counts, and eventually stool cultures and stool examination for parasites.(Bost Med Surg J 1901, 144:175-8)

     Others from Hopkins arrived. James Flexner, pathologist, later director of the Rockefeller Institute, and Llewelyn Barker, later to be chief of medicine at Hopkins, and a pair of medical students plunged into research, one result of which was the description of a new Shiga bacillus causing much of the dysentery, named shigella flexneri after its discoverer.

      A Second Board of Research was established in 1906 under Percy Ashburn and Charles Craig, which lasted considerably longer. This Board made a number of discoveries and elaborated important information. A few examples: Filariasis was first described in the Philippines, originally thought to be  due to a new species, but eventually proved to be Filaria bancrofti; dengue fever was discovered by Charles Craig and Percy Ashburn to be caused by a filterable agent,to be non-contagious, and to be mosquito-transmitted (though an incorrect mosquito was named at first). Craig later was head of the Tropical Medicine Department at Tulane, and Ashburn wrote a text pathology in the tropics and a history of the Medical Department of the Army.  The existence of pathogenic and nonpathogenic amebae, first noted by Schaudinn, was confirmed through both microscopic exam and numerous feeding experiments on prison volunteers (with signed informed consent) done by Andrew Sellards and Ernest Walker. These experiments also delineated the clinical course of amebiasis and uncovered the carrier state (Philipp J Sci 1913, 8:253-330). Sellards went to Harvard, then on to be intimately involved in the development of the French version of the yellow fever vaccine, and Walker came to UCSF to work in the Hooper Foundation where he focused mainly on leprosy(see http://texts.cdlib.org/view?docId=hb0w10035d&doc.view=frames&chunk.id=div00061&toc.depth=1&toc.id=).

       Much effort was expended studying the effect of the tropics on arriving soldiers. It was determined that overall health was seldom affected as long as infectious diseases were avoided, that there was no difference in tolerance to tropical life between blonds and brunettes, and that the use of red-orange underwear (to protect against UV light) made no difference, except that it was less comfortable.(JAMA 1912, 58:998-1002)     

    In addition to military issues, the Philippines were now a U.S. colony and the health of the population was at stake. The Philippine Bureau of Science was heavily involved in this effort. Americans worked hard, for example, to find infectious causes for beriberi, without success. British workers in Malaya had studied dietary factors, gradually focusing on rice polishing and showing that polished rice seemed to be the culprit. The Americans confirmed this idea when their own native scouts developed beriberi and were cured with consumption of unmilled rice, though the exact explanation for this was still obscure (for summary see Carpenter, KJ, Beriberi, White Rice, and Vitamin B, 2000).  

     Victor Heiser arrived as Quarantine Officer with the Marine Hospital Service, later was Health Officer for the Philippines, and dealt with plague, cholera, and smallpox epidemics, the latter suppressed with mass vaccination using material made from caribou. (Phil J Sci 1910, 6:171-9). He later was a major officer in the Rockefeller Foundation's International Health Board. Edward Stitt, a naval surgeon who had studied under Manson and was in the Philippines, wrote the first American text on Tropical Disease, a book that went through six editions and then was taken over by Richard Strong.

Richard P Strong

     Richard Strong, mentioned above, is perhaps the best candidate for the title of the American "father of tropical medicine". In addition to work mentioned, he was the first to show the curative properties of compound 606, which he obtained directly from Paul Ehrlich, in treating yaws, a prevalent disease there (Phil J Sci 1910, 5B:433-54). Strong was called in 1912 to become the first professor of tropical medicine at Harvard. In this capacity he organized several expeditions to Guatemala, South America, and Africa to study tropical disease (as well as local food and cultural practices). In 1915 he headed, through the American Red Cross and Rockefeller Foundation, an expedition to Serbia to combat a massive typhus epidemic, and was part of the Typhus Commission, Medical Research Committee, American Red Cross, that established the louse transmission of trench fever during WWI (Avail. at Hathi Trust). In WWII he served as director of tropical medicine at the Army Medical School. The only blemish on his career was an accidental infection of prisoners with plague during a trial of a cholera vaccine (Rev Inf Dis 1989, v11: 996-1004). He needs a good biography. 

     I could go on, but this is enough to indicate the role of the American occupation of the Philippines in the creation of tropical medicine as a specialty in the U.S. The origin of the American Society of Tropical Medicine is another, and interesting, story for a future blog.