THE LITTLE APPENDAGE

     Wait a minute – don’t take out that appendix!

     This sounds like heresy, but a recent article in JAMA (June 16, 2015) showing the near equivalency of antibiotics and surgery as treatment for appendicitis suggests a non-surgical approach as an alternative. Controversy over the appendix and appendicitis is hardly new, but how far back does it go?

    Berengario daCarpi, the famous anatomist and the first to describe anatomical structures based on his own human dissections, is credited with the first description of the appendix (1521). 
     Leonardo da Vinci included it in earlier anatomic drawings, but they were not published until the 18^th century. His translated comment on the structure is: "The auricle (appendix) n, of the colon, n m, is a part of the monoculus (caecum) and is capable of contracting and dilating so that excessive wind does not rupture the monoculus." (See right lower part of drawing.)

By Leonardo da Vinci, probably 1504-6. From Leonardo da Vinci on the Human Body by C.D. O'Malley and  J.B.de C.M. Saunders, 1952. Courtesy Hathi Trust.

From Vesalius' De Fabrica, Book 5. (Courtesy Biu Sante,Paris)

Vesalius showed the appendix clearly. He felt it should be called the caecum but the name appendix prevailed. 


     After experiments in removing the appendix (in animals) and noting its absence in certain animals it was later deemed to have no important function. Rare cases of perforated or gangrenous appendix were described at autopsy in the 18^th century, including one by John Hunter. More cases followed, and in 1827 Francois Mêlier described four fatal cases plus two from another surgeon, all showing at autopsy abdominal pus and a diseased appendix adjacent to an apparently healthy caecum. Mêlier was the first to suggest the possibility of surgery for the condition. 

Guillaume Dupuytren.  (From Wikipedia and Wellcome  Images)

     His opinion, however, was contradicted by Guillaume Dupuytren, the most prominent surgeon of the time, who felt that a diseased caecum was the culprit. Dupuytren’s exalted status and his abrupt personality apparently finished the argument, though it was largely academic since surgeons rarely ventured into the abdomen. Richard Bright and Thomas Addison, however, in their 1839 text (Elements of the Practice of Medicine) specifically mention “ulceration….of the vermiform process of the caecum” as a cause of acute peritonitis, as did occasional other writers. Names like “typhlitis” (cecal inflam-mation) and “paratyphlitis” (peri-cecal inflammation/pus) were given to the clinico-pathologic picture.        

Reginald Fitz. (From Nat. Library of Medicine)

     The issue was laid to rest by Reginald Fitz, professor of pathological anatomy at Harvard and a practicing surgeon. He had studied with Virchow (and others) in Europe and introduced the microscope into the Harvard medical school curriculum at the time of Charles Eliot’s presidency. His 1886 article in the American Journal of the Medical Sciences laid out the clinical and pathologic features of the disorder, using the word “appendicitis” for the first time, after which the vagaries of “typhlitis” and “paratyphlitis” died out. Most important, he recommended removal of the appendix as treatment. Other surgeons concurred, and contributed to raising appendectomy from a rare to a relatively common operation over the next decade. This was the age of anesthesia and “Listerism”, and a reduced fear of abdominal surgery.

     But the first surgeries had mixed results and controversies arose about when to operate, how to make the incision, how to predict perforation, and so on. William Osler pondered this problem. His extensive autopsy experience had taught him that appendicitis could heal by itself, or could resolve and recur. In the first edition of his text, 1892, he advised that "severe" cases have surgery. In mild cases it depended in part on the availability and skill of the surgeon, though he recognized that predicting perforation was chancy. On the other hand, he said, medical treatment could “be expressed in three words – rest, opium, and enemata”. Four years later, in the second edition, Osler was admitting cases directly to the surgical ward, warning that delays in surgery could be fatal, even though results from surgery were only fair at the time. Harvey Cushing's case (see below) illustrates the dilemma.  
     In Osler’s time the press had extensively publicized appendicitis, extolling the marvelous wonders of surgery, something Osler commented on in the 1896 edition: “There is a well-marked appendicular hypochondriasis (italics mine). Through the pernicious influence of the daily press, appendicitis has become a sort of fad, and the physician has often to deal with patients who have a sort of fixed idea that they have the disease. The worst cases of this class which I have seen have been in members of our profession…”
     Results improved over time and surgical treatment has prevailed until the present - now perhaps to be replaced by antibiotic therapy in early cases.

     

     A couple of interesting “appendicitis anecdotes”:

    1)  Harvey Cushing, as a resident at Hopkins, developed appendicitis and was operated on by William Halstead and two other surgeons (Finney and Bloodgood), with a slow recovery.

Harvey Cushing by Edmund Tarbell, from Wikipedia

Cushing wrote out his own history and examination (see insert). Fulton, his biographer, says, “The new operation had been performed several times at the Hopkins prior to his (Cushing’s) advent in Baltimore, but the results had not been particularly encouraging and Halstead was still reluctant to recommend it.” Halstead had little experience with it, in fact. Cushing knew this but pushed to operate, and left instructions with a friend on how to distribute his things in case of death.

     

{From Fulton's life of Cushing (Google Books)}

  2)  The coronation of King Edward VII, following the death of Queen Victoria, was scheduled for June 26, 1902. Fourteen days before, Edward developed abdominal pain and fever. He was seen by several physicians and improved with general measures. After a large pre-coronation banquet on the 25th Edward’s symptoms relapsed severely, and he was told by Sir Frederick Treves (and four other physicians in attendance) that he needed immediate surgery. When he protested that he had to attend his coronation, Treves told him, “Then, Sir, you will go as a corpse.” At surgery an abscess was opened and drained, and the appendix left in. He recovered. Treves was made a Baronet and accumulated a huge private practice, though his daughter, ironically, died of appendicitis.

Works consulted:

Smith, Dale: “Apendicitis, Appendectomy, and the Surgeon”. Bull Hist Med, 1996. v 70:414-441.

Melier, F: “Memoire et Observations sur Quelques Malades de l’Appendice coecale”. J Generale de Medecine, de Chirurgie, et de Pharmacie 1827, p 317.

Fitz, R. “Perforating Inflammation of the Vermiform Appendix”. Amer J Med Sci. 1886, 92:321-346.

Williams, G R. A History of Appendicitis. Ann of Surgery 1983. 197: 495-506.

Osler, William: Principles and Practice of Medicine, 1892 and 1896.

Fulton, J. Harvey Cushing: A Biography. 1946.

Bliss, Michael. Harvey Cushing: A Life in Surgery. 2005.

C D O'Malley, J B de C M Saunders: Leonardo da Vinci on the Human Body, 1952 (available at Hathi Trust web site)

     

PASTEUR and the ART WORLD

     What does Louis Pasteur have to do with the art world?

Quite a lot, it turns out.

    Thanks to the publications of the historian of medicine and science, Bert Hansen, and a former student and collaborator of his, Richard Weisberg, we have a window on an aspect of Pasteur’s life that has been neglected or overlooked. Pasteur displayed a keen interest in art, had artistic sensibility of his own, cultivated friendships with artists, and frequently helped them in their careers.

     As a teenager Pasteur studied art in his hometown of Arbois and then at Besancon, working mainly in pastels. Examples of his work, quite accomplished for his age and showing an appreciation for facial detail and expression, can be seen at http://orphea-linux.sis.pasteur.fr/index2.pgi. (click on Pasteur: oevre artistique)

     Pasteur went on to study physics and chemistry, obtain his degrees, marry, and fill various teaching and research positions until 1858 when he came to Paris permanently. In his travels for research he made a point of visiting art museums. He had an eye for sculpture as well as painting. In 1863, age 41, he began giving lectures at the École des Beaux-Arts, the leading art school in Paris, discussing physical and chemical properties of pigments, paints, and related materials. There he befriended a number of current and future artists.

     In those days most artists made their reputation by being accepted into the Paris Salon, a huge annual exhibition sponsored by the French Government. It was a juried show (with some established artists grandfathered in), opening May 1, lasting 6-8 weeks, and accepting between 2,000 and 5,000 works. Pasteur visited the Salon regularly, studied the press reviews, and knew some of the artists.

"Solitude" by Jean-Jacques Henner

      One of his close friends was the artist Jean-Jacques Henner. Henner, less well-known today, was a leading artist in Pasteur’s time, regularly exhibited in the Salon, a member of the Académie des Beaux Arts (which was limited to 40 seats, 14 of which were reserved for painting), and a winner of a number of awards. He is known for portraits and for scenes of women in somewhat spiritual settings. His work hangs today in the d’Orsay, National Gallery, Hermitage, and the Cantor Museum at Stanford (see insert). Pasteur entertained Henner in his home and on one occasion asked him to put in a good word for another artist at a Salon showing.

     Pasteur also took an interest in sculpture, which led to a warm relationship with the sculptor Jean-Joseph Perraud. Perraud too had won numerous awards, was in the Académie, and had been made a Chevalier of the Legion of Honor. He did a bust of Pasteur for which he refused payment, and when he was ill Pasteur helped secure medical care for him. Pasteur spoke at his funeral and later delivered a second eulogy at the unveiling of a bust of the artist in his hometown of Monay, done by a former student.

     The sculptor Paul Dubois and Pasteur knew each other well. They had both been guests of honor of the Emperor and Empress at a royal chateaux in 1865, and Dubois had won a number of honors and commissions.  A famous full-length work is his “Florentine Singer”(visible at: https://www.google.com/culturalinstitute/asset-viewer/a-fifteenth-century-florentine-singer/MQE_A8SRHMGNUw?hl=en). But  Dubois was most known for portrait busts, and executed one of Pasteur, commissioned by the Danish  brewer Jacob Christian Jacobsen. After the Franco-Prussian War of 1870 Pasteur, partly as an anti-German move, began studies to improve beer brewing. Beer spoiled easily, yeasts were hard to maintain, and so forth, and Pasteur cleared up many of these problems. The Danish brewer, Jacobsen (owner of Carlsberg Brewery, named after his son, Carl), was one of the first to utilize Pasteur’s research to upgrade his brewing techniques. He became hugely successful and established a laboratory for research on the science of brewing, now called the Carlsberg Laboratory. Results of all research were to be made public. To show his appreciation to Pasteur Jacobsen commissioned Dubois to sculpt a bust of the scientist. The original marble version was completed in 1879, shown at the Salon in 1880, and then placed in the new laboratory. A plaster copy went to Pasteur and a bronze copy was installed by Jacobsen’s son, Carl, on the exterior of his brewery (viewable at: https://www.flickr.com/photos/egdrossell/14671473537 ). Yet another copy, in bronze, was awarded to the Rockefeller Institute in 1909 by the Pasteur Institute in thanks for assistance in a meningitis outbreak in France. This was in fact a pandemic of meningococcal meningitis that began in New York in 1904-5 and then spread to Europe. Simon Flexner of the Rockefeller Institute had determined that anti-meningococcal serum prepared from immunized horses reduced the mortality rate considerably when injected intrathecally (the fluid space around the spinal cord), especially if given early. Large quantities were manufactured by the Rockefeller Institute and sent to a variety of countries, including France.

Pasteur in his Laboratory

     A few final words about another artist friend, Albert Edelfelt. Originally from Finland, he migrated to Paris, training at the École des Beaux Arts. Introduced by Pasteur’s son, he and Pasteur became close friends and Edelfelt over the years painted portraits of Pasteur and several members of his family. The portrait of Pasteur, painted in 1885 (insert), reveals him in his laboratory peering at a jar containing a drying rabbit spinal cord. While posing for the painting Pasteur was working actively on developing a rabies vaccine but the first case of preventing rabies in a human, that of Joseph Meister, was not until July of that year, just after the painting was finished. The work was entered in the Paris Salon in May of the next year, by which time Pasteur was an international hero, and it enhanced his fame even more. It was pioneering for its time in that the subject is not looking at the viewer nor is he in a chair or other posed setting. Rather he is concentrating on his work and the painting radiates this intensity of thought. A copy was made by the artist for Pasteur while the original was purchased by the French government and held at Versaille for many years until it was placed in the Museé d’Orsay, where it hangs now.

     I'll stop here, mentioning only that the cited articles tell of other artists in Pasteur's life. Pasteur enjoyed art, had an appreciation for it (though he appears not to have been interested in impressionism), welcomed artists as friends, and developed close relationships with several. A good balance to his intense scientific work.

Some works consulted:

  

Hansen and Weisberg: J Med Biography, May 29, 2015. (two articles)

Weisberg and Hansen: Bull Hist Medicine 2015. v89: 59-91 (on Edelfelt)

Hansen. Lecture before American Osler Society, 2014.

Debré, Patrice. Louis Pasteur. 1998 (Eng trans)

Flexner, S. J Exper. Med. 1913, v17: 553.

Pilgrim Haven to Hospital:

Ospedale Santa Maria della Scala
(Re-posted - somehow it got deleted)

     If you travel to Siena don’t miss a visit to the Ospedale Santa Maria della Scala. The latter part of the name derives from the steps of the cathedral next door.

     A feature of medieval and early Renaissance times was a pilgrimage to a holy site. In Europe the three principal destinations were Jerusalem, Santiago de Compostela (burial site of St. James), and Rome (burial site of St. Peter). The route to Jerusalem was closed after the Muslim takeover, but the other two routes remained open. Pilgrimages were popular, not only for religious reasons but because the journey earned a remission of sins and an easier entry into Heaven. The journey was fraught with hazards, including illness, injuries, and banditry.

     The principal north-south route, called the Via Francigena, ran, in its full extent, from Canterbury through Siena to Rome. The Archbishop of Canterbury documented his journey in the late tenth century, but it existed well before then. To accommodate weary, hungry, or ill pilgrims a large number of hostel/hospitals sprang up. A prominent one was Ospedale Santa Maria della Scala, which functioned as a hospital until 1990, over 1000 years. 

     Legend has it that the Ospedale was founded by a poor cobbler named Sorore, but the first documentation is dated 1090, labeling it as a “xenodochium et hospitalis” – a hostel and hospital. The term “xenodochium” goes back to early Byzantium when it referred to a hostel or shelter for the poor, while the “nosokomeian” (“hosptialis” here) functioned specifically to care for the sick. Later, on the pilgrim routes further west, the two functions appear to have been combined. Churches and monasteries were the main early providers of ospedales, but the clerical function of caring for the sick was gradually taken over by secular healers, and was officially ended in 1130 at the Council of Clermont. This corresponded with the rise of the secular medical school in Salerno and the rise of universities elsewhere. In 1193 a papal bull by Celestine III removed all Cathedral control over Santa Maria della Scala. The first lay rector was in 1200.

     Over time the Ospedale became a large concern, and self-sufficient. Through generous bequests and purchases it acquired or built numerous farms, granaries, and small ospedales in the surrounding countryside, eventually becoming one of the biggest landowners and economic entities of the State. The size concerned the State authorities, enough to insist in 1433 on being the ones to nominate the Rector, whom they could control.

     In addition to assisting pilgrims the Ospedale cared for the sick in general. Trying to cure patients rather than simply comforting them was an early goal. A physician, a surgeon, and an apothecary were kept as salaried employees. Surprisingly, for the times, there was only one patient per bed and the beds were covered with sheets, changed if dirty. In time student physicians and surgeons assisted in the work and more specific medicines were used, such as Peruvian bark. Nutritious diet (and wine) was provided, most from their own farms.

     Another function included the care of foundlings, a common problem. In 1298 there were over 300 under care, increasing to 1212 in 1618. The mortality rate of the infants was high. Identifying objects and records were kept in case the parents showed up later to reclaim the child. The infants were first handed over to wet nurses, then brought back in and educated in a trade (the boys) or sewing and weaving (the girls). Any earnings from their work were saved for the time of discharge at age 18, if they wanted to leave, and for girls money was granted as a dowry or to enter a convent.

     Finally, not losing sight of its religious origins, the Ospedale dispensed food to the poor three times a week, the Rector himself presiding on feast days.

Pellegrinaio (photo by author)

     This being Siena, art was not neglected. The front façade was originally covered with fresco, but the surface has been lost. In the interior, frescoes decorated various chapels, but to the medical historian the most fascinating are the frescoes of the “Pellegrinaio” – the Pilgrims’ Hall. The photo nearby shows the large hall, an open ward up until 1983, whose walls are covered with 15^th century murals, beautifully preserved. Most are painted by Domenico di Bartolo, the tutor of Piero della Francesca, and illustrate numerous details.

     You can zoom in on the pictures.

Caring for the Sick (photo by author)

   
     Look at “Caring for the Sick” (1440-1). In the center the Rector and some oblates of the hospital are next to a surgeon examining a man with a cut in his right thigh. To the left is a patient being eased onto a stretcher and two doctors examining a container of urine. On the right is a priest hearing confession and attendants are carrying a stretcher. The architectural details are said to be accurate.

Distribution of Alms (photo by author)

     Next, look at “The Distribution of Alms” (1441). In the center an almost nude man is being clothed, on the right bread is passed out (a woman with a baby already has her basket), and a cripple waits on the ground. On the left the Rector is taking off his hat in deference to a nobleman, probably an important benefactor. The background is a church within the Ospedale.

Payment to the Wet Nurses with Money (photo by author)

     “Payment of to the Wet Nurses with Money” was painted later, in the 16^th century, after an addition to the hall, by Metro d’Achille Crogi and Giovanni di Raffaele Navesi. Wet nurses were paid in grain or money, and the painting shows the monetary payment and the care of the foundlings. The purpose of the two large men is not clear to me.

     The Ospedale modernized with the times and functioned as a full hospital until 1990, when it was transferred to a large, modern building on the edge of the city. The old building is now a museum, still in the process of discovering all its ancient treasures, only a brief glimpse of which I have given.

     The Ospedale maintains a web site showing more details of the paintings and other treasures inside the building complex: http://www.santamariadellascala.com/w2d3/v3/view/sms2/storia--22/index_en.html

 Other reproductions are available at:

http://www.wga.hu/html_m/d/domenico/bartolo/pellegri/

Works consulted:

     Baron, JH: The Hospital of Santa Maria della Scala. BMJ 1990. v301, pp 1449-51

     Risse, GB: Mending Bodies, Saving Souls: A History of Hospitals. Oxf Univ Press,  

     1999.

     Museum-published book on the Ospedale.

Bologna

     Greetings from Bologna, an ancient city, dating back to the Etruscans if not earlier. Its University is among the oldest in Europe, said to have been founded in 1088, a place where early pioneers in medicine are to be found.  It consisted originally of a law school – both canon law and civil law (Copernicus studied canon law here), followed by the School of Philosophy, each unit known as a Studium. Medicine is thought to have entered the curriculum in the early 13^th century, and was incorporated into the Philosophy Division (typical of other Italian universities). The Studium included the study of Aristotle, medicine, astrology, mathematics, rhetoric, and what we would call the “arts”. Aristotle in northern Europe was taught as speculative philosophy, while in northern Italy it was taught as a basis of medicine. The above arts, including disputation and dialectic, were considered necessary in medicine.

     It was a time when works by Aristotle, Galen, Hippocrates, and Arab physicians, through translations from Arabic and Greek, were entering Europe. Only limited works by these authors had been available before. Shaping these works into an organized medical curriculum was accomplished by Taddeo Alderotti. Nephew of a surgeon, he studied in Bologna, and by the 1260s he was teaching medicine at the University.  His consolidated curriculum became a standardized body of works serving as a basis for examination and licensing, and leading to the first formal “College of Physicians”. (Others followed, and served as a template when Thomas Linacre secured a charter from Henry VIII in 1518 to form the Royal College of Physicians.) The reading included the Aphorisms of Hippocrates, the Canon of Avicenna, and works by Galen and Arab physicians, along with a work of his own: the Consilia, a collection of clinical cases with advice on how to treat them. Taddeo was known for his high fees (nothing new!). Pope Honorious IV was a patient of his.    

     One of Alderotti’s students, Mondino di Luzzi, an anatomy professor, was the first to dissect human cadavers, with permission from a Church that now considered anatomy part of “natural philosophy” – a study of God’s creation.(1) Most important, Mondino published an anatomy text in 1316 (based almost entirely on Galen) that was a standard text for the next 200+ years. Unfortunately it contained little that was new but it stimulated further dissection and emphasized anatomy’s importance in medicine (as Galen had emphasized). It was really a manual, the first of its kind, designed to be read aloud while the cadaver, an executed criminal or a body stolen from a grave (11), was dissected over three or more days by a surgeon, proceeding from the abdomen and reproductive organs upward (to minimize putrefaction). In line with Aristotle’s idea of “final cause” and man’s body as God’s perfect creation, every structure had a function.

     Surgery was part of the curriculum, unlike in northern Europe. The Dominican Friar Theodoric Borgognoni, a contemporary with Alderotti, studied medicine in Bologna and was a surgeon as well, probably learning much of it from his surgeon father. His works are known for the advice that pus in wounds is not desirable, the use of wine on wound dressings, and the use of sponges soaked in opiates and placed over the nose to induce some narcosis.

Image of brain from Isagogae breves

     Roughly 200 years later Berengario da Carpi, professor of surgery at Bologna, wrote an update on Mondinus’ text (called a “Commentary”), followed in 1522 (the year after Pope Leo X excommunicated Martin Luther) by a masterful anatomy manual of his own, entitled Isagogae breves, or “Short Introduction” (to anatomy). The latter is said to be the first illustrated anatomy book, and reflects the author’s attention to human dissections rather than ancient texts (Galen dissected apes and other animals) in that he described new structures including the brain’s ventricles, the foramen ovale, the appendix, and several other structures absent from Galen and Mondinus. It was a major advance and laid the groundwork for Vesalius’ masterpiece in 1543 (Vesalius did not credit Berengario). Several of the poses in Vesalius’ work are thought to be modeled on those seen in Berengario’s manual.

     Several years later Giulio Cesare Aranzio, professor of surgery and anatomy at Bologna, established anatomy as a separate department, retaining himself as chief of both. He described several structures including the hippocampus. He also wrote a book on the human fetus, which included good descriptions of the fetus and gravid uterus.  Aranzio, as a surgeon, was unusual for performing rhinoplasties, an operation known in ancient India which resurfaced in southern Italy and, in improved form, was made famous by the Viraneo family in the small Calabrian town of Tropea. Knowledge of the procedure made its way to Bologna, where Aranzio took it up. Aranzio’s pupil, Gaasparo Tagliacozzi, adopted and improved the technique and wrote a book on it, though failing to give any credit to his professor, Aranzio. In spite of what appears to have been favorable acceptance of the operation, it died out shortly after Tagliacozzi’s death in 1599. In the procedure, a skin flap was taken from the upper arm to the nasal area, the arm held near the face with an awkward contraption (see figure) until the flap appeared viable, then the flap was severed from the arm, all without anesthesia. Tycho Brahe, the astronomer, who lost his nose in a sword fight in 1566 and had a metal replacement made, was a contemporary. Whether he was aware of this procedure is unclear.

Gasparo Tagliacozzi

Apparatus for nose replacement

     Of particular interest in the 16^th and 17^th centuries in Bologna medicine is the creation of a tribunal to regulate and supervise the practice of medicine – the Protomedicato. Comprised of rotating members of the College of Physicians, it assumed the civic functions of inspecting pharmacies for improper drugs, licensing lower-level practitioners (the College licensed full physicians, surgeons, etc), prohibiting treatments thought to be harmful, and pursuing other “public safety” activities. It was particularly careful in supervising the production of theriac, a remedy for almost anything, including poisoning. Viper meat was theriac’s main ingredient, and its manufacture was so hallowed and expensive that it was part of a public ceremony.

      The Protomedicato also decided on lawsuits between patients and healers. Before this body a doctor could sue to recover an unpaid fee or a patient could allege that his treatment was substandard. Particularly curious, as described by Gianna Pomata in her book, Contracting a Cure, is the custom of patient and doctor entering into either verbal contracts with witnesses present or written contracts, stipulating the medical complaint, the treatment (including its duration), the expected (or promised) outcome, the fee, and various do’s and don’ts for the patient. Often the fee would be placed with a third party and paid in installments as the treatment proceeded. Suits arose if the patient did not recover as promised, in which case the plaintiff wanted his money back. Over time, however, the College of Physicians drifted into demanding fees for their services, regardless of outcome.

     Perhaps the most unusual professor and physician in Bologna was Gerolamo Cardano (1501-1576), a genius and polymath, whose interest in medicine was one of many. He received his medical education at Pavia and was later professor of medicine there, but after his son (also a physician) was executed for poisoning his wife, he lost his position at Pavia and, through connections, obtained a professorship in Bologna. By then he was famous for other works, such as a pioneering work on algebra (which included a solution to cubic equations and adumbrated imaginary numbers), 2 encyclopedias, works on astrology (he once created a horoscope for Jesus), and works on medicine. Astrology and the occult heavily infused his ideas on medicine and disease. He was also a sharp gambler, supplemented his income through it, and was one of the first to formulate rules of probability. Cardano’s horoscope of Christ eventually got him into trouble with the Inquisition. He spent time in prison, lost his professorship in Bologna, and finally retired to Rome where he wrote his autobiography.

     Moving to the next century, we should mention Marcello Malpighi. Born in 1628, he received his medical training in Bologna, learned to use the microscope (a Galileo model) in Pisa, worked productively at the university in Messina, and became Professor of Practical Medicine at Bologna in 1666. By this time he had found, using the microscope, the capillary circulation and the alveolar structure of the lungs as well as (using injections into renal arteries) the capillary connections to the renal glomeruli. With these and further discoveries he is considered the founder of microscopic anatomy. He was a contemporary of Robert Hooke and Anton van Leeuwenhoek, but outstripped them both with his facility in microscopic anatomy. Other discoveries include taste buds, sensory organs in the skin, respiratory tubules in insects, and more. He also practiced medicine continuously, trying to base his therapies on anatomic findings. Much of his practice was carried on by correspondence, not uncommon at the time. Since physical examinations were almost nonexistent, a history by mail was almost as good as one in the office, and treatments were advised by return mail. This correspondence, and that with his scientific colleagues, were part of a larger endeavor, the “Republic of Letters”, through which new ideas and knowledge were disseminated before journals took over. Malpighi was made a member of the Royal Society and his contributions published regularly. In 1691 he left Bologna for Rome where he was personal physician to Pope Innocenzo XII, and a Professor of Medicine. He died in 1694. He is buried in Bologna.

     There is a fascinating web site that lists medical historical items in cities all over the world. For more on Bologna, go there: http://himetop.wikidot.com/start.

Some works consulted for this essay:

1. Cunningham, A: The Anatomical Renaissance.  1997

2. Pomata, Gianna: Contracting a Cure: Patients, Healers, and the Law in Early Modern 

          Bologna. 1998

3. Siraisi, Nancy: Taddeo Alderotti and His Pupils. 1981

4. Gnudi, MT and Webster, JP: The Life and Times of Gaspare Tagliacozzi. 1950

5. Berengorio da Carpi: Isagogae Brevis, trans by LR Lind, 1959

6. Mondino, Alderotti, Cardano, Malpighi: In Dictionary of Scientific Biography.

7. Bresadola, M: A Physician and a Man of Science: Malpighi’s Medical Practice. Bull

         Hist Med 2011. 85: 193-221

8. Ioli,A, et al: Marcello Malpighi. Am J Nephrology 1993. 13: 223-8

9. Bresadola,M: “A Physician and a Man of Science: Patients, Physicians, and Diseases

         in Marcello Malpighi’s Medical Practice”. Bull Hist Med, 85: 193-221. 2011

10. Castiglione, A. A History of Medicine, 2^nd edit. 1958.

11. Mettler, C C. History of Medicine.1947, p.36.

12. Mezzogiorno, A and P. “Marcello Malpighi”. Amer J Nephrol. 1997. 17: 269.

    

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.