BENJAMIN FRANKLIN’S GOUT

      Benjamin Franklin’s name is recognized everywhere. No American history course omits mention of his accomplishments. Less often referred to, though, is his struggle with gout and urinary stones, maladies that plagued him in later years. 

Benjamin Franklin in a fur hat he often wore 
in France (Wikipedia)

         Franklin first mentioned “a touch of the gout” in a letter to his sister when he was 56 years old. Gout appears off and on in later letters as an annoying but not serious impediment. Franklin, of course, was conversant with many medical and scientific matters, often corresponding with doctors. He knew the writings of Thomas Sydenham, considered the father of English medicine, who had published a treatise on gout in 1683. Sydenham noted that gout “generally attacks those aged persons who have spent most part of their lives in ease, voluptuousness, high living, and too free an use of wine and other spirituous liquors” and “…have

Thomas Sydenham, by Mary Beale
(Wikipedia)

large heads, are generally of a plethoric, moist, and lax habit of body…” When, less often, it attacks younger persons, they received it from gouty parents or occasioned it by “over-early use of venery.” Sydenham also recognized an association with urinary stones, and he discouraged bleeding, emetics, purges, and sweating agents in favor of certain herbal remedies. Leeuwenhoek had seen the needle-like crystals from gouty tophi but identification of uric acid as the important substance came after Franklin’s time.

         Franklin had been sent to France early in the American Revolution to enlist the aid of the French government in the revolt against England. He arrived in December 1776, at the age of seventy. He was well known there, as Voltaire had extolled him as the discoverer of electricity, a genius, a successor to Newton, and a scientist. He took up residence on an eighteen-acre estate in Passy, a wealthy commune near Paris, owned by an aristocrat sympathetic to the American cause. 

Franklin presented at court. Louis XVI and Marie Antoinette are seated on the right. The woman
in white next to Franklin is Diane Polignac, lady-in-waiting to the queen's sister. (Library of Congress)
(click on image to enlarge)

Franklin commuted to Paris for consultations with the French government, during which he faced numerous meals rich in fatty meats, pastries, and wines, many of the latter fortified. He became especially fond of Madeira and consumed generous quantities of it. His gout intensified and he believed that his new lifestyle was responsible. Lead was often present in wine at the time, entering during its production and seeping in from lead-containing wine vessels. Lead can promote gout by decreasing uric acid clearance and is believed to have contributed to Franklin’s case. 

Madame Brillon, by Fragonard (Wikipedia)

Near Franklin in Passy lived Madame Brillon, the wife of a much older and frequently absent man. Madam Brillon was quite attractive, and she and franklin flirted with each other. During one of Benjamin’s gouty attacks, she composed a poem, chiding him for bringing it on himself by eating too much, drinking too much, avoiding exercise, and “you pass your time with dames” (translated).  He subsequently composed a dialogue  between himself and "Madame Gout," who also berates him for dietary excesses and lack of exercise.

Colchicine, known to the ancients as a remedy for gout, seems to have fallen out of favor in Franklin’s time. He probably did not use it, but it was available in Paris as part of a secret formula called “Eau Médicinale.” Colchicine is derived from the plant Colchicum autumnale, or autumn crocus, found most abundantly in Colchis, an ancient tribal area, described by Herodotus, that covered a region corresponding to the western part of modern Georgia. The identity of colchicine as the secret ingredient in Eau Médicinale was revealed in 1814 and its use in gout subsequently reaffirmed.

Aside from gouty attacks in his feet, Franklin had passed “gravel” in his urine off and on, but it was not until he was 76 that he became aware of a bladder stone that would not pass. The stone troubled him principally when traveling in a coach or walking and he limited his activities to avoid excruciating pain. This hampered his negotiations over the Treaty of Paris of 1783 ending the American Revolutionary War. He medicated himself with large amounts of honey, molasses, and jellies, hoping that they would increase the specific gravity of the urine and allow the stone to be buoyed up and perhaps keep gravel from coalescing. His idea stems from a school of thought known as iatrophysical or iatromechanical medicine, seeking to explain physiological processes through the laws of physics. He could not know the modern conception of urine and stone formation.

Doctors advised another medication for the stone, Blackrie’s Lixivium, a solution of salt of tartar (potassium carbonate), quicklime (calcium oxide) from oyster shells, and water, which is basically a lye solution. Prescribers of this remedy, a remnant of the iatrochemical school of thought, hoped that the lye would dissolve stones. Surgery was discussed among his doctors but dismissed as unreasonable. The operation would have been a lithotomy, removing

John Jones, surgeon (National Library 
of Medicine)

the stone through an incision between the scrotum and the perineum, without anesthesia. Founding father and later chief justice John Marshall underwent this procedure in his sixties, successfully. His surgeon was John Jones, a prominent surgeon in the American Revolution, the first to perform a lithotomy in America, and one who could accomplish the surgery in a little over one minute, to minimize pain.

Franklin returned to America in 1785 in ever more pain from the stone. He finally resorted to opiates, which eased the agonies somewhat. He signed the new U.S. Constitution in 1787 but eventually, with John Jones attending him, succumbed to a lung abscess in 1790 at the age of 84. Alert to the end, he lived a remarkably long life for his era, and certainly a productive one.

 

SOURCES:

 

Corner, GW and Goodwin, WE, “Benjamin Franklin’s Bladder Stone.” 1953; J Hist Med Allied Sci8: 359-77.

 

Finger, S and Hagemann, IS, “Benjamin Franklin’s Risk Factors for Gout and Stones: From Genes and Diet to Possible Lead Poisoning.” 2008; Proc Amer Philosoph Soc 152 (2): 189-206.

 

Franklin, JL, “The Three Contraries of Benjamin Franklin: “the gout, the stone, and not yet master of all my passions.” 2021; Hektoen 13 (3).

 

Franklin, B. The Bagatelles from Passy. 1780; Facsimile by Eakins Press, New York, 1967 (Originally printed by B. Franklin on his personal press at Passy).

 

Griesemer, A D, et al, “John Jones, M.D.: Pioneer, Patriot, and Founder of American Surgery.” 2010; World J Surg. 34 (4): 605-9.

 

 

                                    EISENHOWER’S HEART 

      At about two AM on the morning of September 24, 1955, a severe chest pain awakened President Eisenhower. Thinking it related to a giant hamburger with onions eaten the day before, he got up to find some milk of magnesia. Mamie, hearing the noise, came in and, alarmed at her husband’s appearance, called their family physician, Dr. Howard Snyder. Dr. Snyder, residing nearby, arrived at about 3 AM at the home of Mamie’s mother, outside Denver, where the couple were staying. Eisenhower had suffered from abdominal

General Snyder, Eisenhower's personal
physician (Wikipedia)

pains for years, all through WWII in fact (with no clear diagnosis), and Dr. Snyder apparently thought this might be a manifestation of his usual disorder. He administered morphine which helped the pain. Events thereafter are confused due to differing reports, but it is safe to say that sometime in the late morning Snyder suspected a cardiac origin of the pain and called nearby Fitzsimons Army Hospital, requesting an EKG machine. The commander of the hospital and the chief cardiologist, Dr. Byron Pollock, came and quickly diagnosed an anterior myocardial infarction. 

         Ike was helped down the front stairs into the presidential limousine, driven by a circuitous route to avoid the press, and delivered to the back door of Fitzsimons Army Hospital. Once in bed, covered by an oxygen tent, he received more morphine, along with papaverine (thought to open up the coronary arteries), atropine (thought to help prevent arrythmias), and heparin, followed by Coumadin (for anticoagulation). Dr. Thomas Mattingly, chief of cardiology at Walter Reed Hospital and Dr. Paul Dudley White, who had been a mentor of Mattingly and was at the time probably the best-known cardiologist in the country, were called in for

Paul Dudley White, seated, next to Ancel Keys,
early advocate of Mediterranean diet, standing.
(National Library of Medicine)

consultation. They all concurred on the prescribed regimen. Eisenhower, unhappy about the previous cover-ups of the illnesses of FDR and Woodrow Wilson, ordered that the public be informed of events.

         Interestingly, during the previous few days Eisenhower had been fishing near the continental divide, at about 8900 feet, without any chest complaints. His blood pressure was known to be mildly elevated at times, especially when angry. His cholesterol was about 200, he was not overweight, he exercised regularly and, though previously a heavy smoker, he had given it up abruptly in 1949.

         The choice of Paul Dudley White (“P. D.” to friends) as the civilian consultant was a fortunate one. White was a founder of the American Heart Association, author of numerous books, including a standard textbook on cardiology, and a physician consultant to a number of celebrities. He had transported to the Massachusetts General Hospital their first EKG machine from the laboratory of Dr. Thomas Lewis, in London, in 1914. Equally important, White was smooth and tactful with the press.

         Eisenhower was not treated in a cardiac care unit at Fitzsimons. In fact, treating heart attacks at home was still a common and recommended practice. The first CCU in the world opened seven years later, in Kansas City in 1962. The essential components of a CCU, such as external pacemaking, electroshock for ventricular fibrillation, and closed chest massage for cardiac resuscitation were not worked out until 1960. Monitoring with oscilloscopes was possible, and drugs such as quinidine, procainamide, and digitalis were available, as was anticoagulation. CCUs proliferated worldwide once the necessary elements were in place. 

         Eisenhower’s clinical course was fairly smooth, though the infarct was a large one. Six weeks of bed and chair existence was the favored regimen at the time, followed by a gradual increase in exercise. Eisenhower left the hospital after seven weeks. About nine months later, he developed an intestinal obstruction, relieved by surgery, at which time the diagnosis of regional ileitis, or Crohn’s

Dwight Eisenhower during his second term
(Wikipedia)

disease, became apparent. It was certainly the reason he had had so much intestinal distress over the years. After a somewhat slow but steady recovery, Eisenhower ran for a second term as president and completed his time in office without major medical problems.

         In November 1965, now retired and in Georgia, Ike had another, milder, attack. After stabilization, he was transferred this time to a modern CCU in Walter Reed Hospital, where he stayed five weeks, still on the bed and chair regimen. Two and one-half years later, in California, recurrent chest pains landed him in the hospital at March Air Force Base from where he was flown back to Walter Reed. This infarction was complicated by multiple episodes of ventricular fibrillation, uncontrolled by drugs. It required a total of fourteen external shocks to Eisenhower’s chest before the rhythm settled down. “He died fourteen times,” it was said. Amazingly, he remained alert and calm through most of the ordeal. 

Walter Reed Hospital (Wikipedia)

But the old soldier’s time was running out. Before he could be discharged, another intestinal obstruction prompted a second operation that he endured successfully, though it weakened him. His heart failed to rally after the surgery, and he expired quietly on March 28, 1969. An autopsy confirmed extensive three-vessel coronary disease and scarring of the heart muscle. His final stay in Walter Reed Hospital had lasted for approximately ten months.

         Dwight Eisenhower’s staff generally reported his medical problems correctly, as he had asked, though sometimes minimizing their severity. And, importantly, Ike’s cardiac illness helped promote awareness and knowledge of heart disease among the general public.

P.S. Please visit the informative History of Medicine Museum of the Sierra Sacramento Valley Medical Society at: http://www.ssvms.org/museum.aspx

The exhibits and essays are well worth it.

 

SOURCES:

Lasby, Clarence G., Eisenhower’s Heart Attack: How Ike Beat Heart Disease and Held on to the Presidency. Univ of Kansas Press, 1997.

 

Diamond, E. Grey, ed., Paul Dudley White: A Portrait. Reprinted from Amer J Cardiology, 1965.

 

Fye, W. B., “Resuscitating a Circulation Abstract to Celebrate the 50^th Anniversary of the Coronary Care Unit Concept.” 2011; Circulation, 124: 1886-93.

 

Caswell, J.E., “A Brief History of Coronary Care Units.” 1967; Pub Health Reports 82 (12): 1105-7.

 

Herrick, J.B., “Concerning Thrombosis of the Coronary Arteries.” 1918; Trans Assoc Amer Physicians 33: 408-18.

         

  

CHRISTMAS DISEASE

 

 

         In the final issue of the British Medical Journal for 1952, an article appeared with the intriguing title: “Christmas Disease: A Condition Previously Mistaken for Hemophilia.” The authors described a new bleeding disorder found in seven patients. Case number one was a five-year-old boy named Christmas (not stated if this was a first or last name), who had suffered several bleeding episodes after play-induced injuries. All seven cases were indistinguishable from standard clinical hemophilia except that, strangely, bleeding could be stopped by transfusion of plasma taken from hemophilic patients. The authors explain the name given to the disorder, noting that the practice of naming diseases after patients was introduced by Sir Jonathan Hutchinson and had the advantage that “no hypothetical implication is attached to such a name.”

Jonathan Hutchinson was born into a Quaker family in northern England. He was apprenticed briefly to a local doctor, attended

 Jonathan Hutchinson (Wikipedia)

medical school in York, and, in 1850, finished medical training at St. Bartholomew’s Hospital in London. There he befriended other Quakers, such as Thomas Hodgkin, Joseph Lister, and Wilson Fox (later physician in ordinary to the queen), the latter two still in medical school. He became a member of the Royal College of Surgeons and opened a practice. He joined the staff of the Royal London Ophthalmic Hospital, where one of his assistants was Warren Tay, first describer of Tay-Sachs disease, and he attended at the Blackfriar’s Hospital for Skin Diseases. In this way he accumulated broad clinical experience, earning a reputation as a “generalized specialist.” He became an authority on syphilis, wroting a large book on the subject, and created the Archives of Surgery, a journal lasting a decade that was truly his own since he wrote virtually all the articles. 

 Skin cancers arising in arsenic-related keratitis (from Hutchinson's Archives of Surgery,
1890, v 2. (Hathi Trust)

           With a friend, he resurrected the expired Sydenham Society as  the “New Sydenham Society.” It brought translated European medical works (and writings of British authors) to British doctors. He persuaded the British Medical Association to open a medical museum, edited the British Medical Journal for a time, and even opened his own private museum (focusing on natural history), a sign of his passion for collecting. He started a postgraduate school where practitioners, from home and abroad, could be brought up to date on the latest findings. This endeavor floundered, however, from lack of interest.

         He is known for two failings. Although a keen observer and ardent collector, he did not investigate, as did the great surgeon and collector, John Hunter, with whom he was often compared. Secondly, he inexplicably insisted that leprosy was caused by the consumption of spoiled or rotting fish, even after the discovery of the causative organism was widely accepted. The breadth of his clinical acumen is what impressed colleagues, though. He was, as William Osler put it, “the last of the polymaths, the man at home in all spheres of medical practice.”

         What about naming diseases after patients? Hutchinson, an astute observer, is said to have published over 1000 case reports and, indeed, many contained names coined after patients. Examples are Mortimer’s malady (later considered sarcoidosis), Penman disease, Hilliard’s lupus, and Branford legs. Readers of his reports often reversed the process and invented eponyms in the Hutchinson name. “Hutchinson’s triad” is known to medical students as designating three features of congenital syphilis, one of which is “Hutchinson’s teeth,” (notched and small central incisor teeth). Hutchinson’s facies, Hutchinson’s angina, Hutchinson’s patch, and others placed his name for posterity in various publications. 

         

          But back to Christmas disease, which is of great historical interest. As knowledge of genetics and hematology progressed, “Christmas disease” took the name factor IX deficiency or hemophilia B, a sex-linked recessive bleeding disorder carried by females but affecting males almost exclusively. It constitutes about 15-20% of hemophilia cases. This disorder was a burden on royal families, the afflicted males all descending from Queen Victoria. Queen Victoria’s granddaughter, Princess Alexandra, married to Tsar Nicholas II of the Romanov family, had a son, Alexei, heir to the throne, who bled easily. The family's bodies were unearthed from a grave near the Ural town of Yekaterinburg in 1979. Forensic DNA

Female carriers and males are shown. Maurice is the only male not to die of bleeding. (Wikipedia)  

studies showed them to be members of the Romanov family. Samples from the exhumed body of Alexander III, Nicholas’s father, and from living descendants were examined to confirm the relationships. Remains of two of the royal children were missing, however: Alexei, the potential heir, and Anastasia. Only in 2007, were bone fragments found buried nearby that proved on DNA analysis to belong to the two missing children. Further study revealed that Alexei had the genetic mutation characteristic of factor IX deficiency, or Christmas disease.

         The mutation exerted tragic effects on descendants of Queen Victoria. One son, two grandsons, and five great-grandsons died of excessive bleeding. The remaining great-grandson, Alexei, was murdered before the disease took its course. One can only speculate on what other avenues history might have taken if the family had not been plagued by the bleeding disorder. Victoria’s own son, Leopold, grew old enough to marry and have a child, but at age 30 he had a fall, dying while his wife was pregnant with their second child. Prince Maurice, son of Victoria’s daughter Beatrice (a known carrier), died on the front in WWI, and probably did not have the disease, or at most a very mild form. No antecedents to Queen Victoria with the altered gene have been discovered and it is presumed that a spontaneous mutation occurred in her genes or those of the immediate prior generation.

 

         But enough of this melancholy narrative on Christmas disease. More joyfully: Merry Christmas and Happy Holidays to all!

 

SOURCES:

Biggs, R. et al, “Christmas Disease: A Condition Previously Mistaken for Hemophilia.” Brit Med J, 1952; Dec 27: 1378-82.

Van Ruth, J and Toonstra, J, “Eponyms of Sir Jonathan Hutchinson.” 2008; Int J Dermatology 47: 754-58.

The Moscow Times, July 16, 2018 (online at: https://www.themoscowtimes.com/2018/07/16/investigators-confirm-authenticity-tsar-nicholas-ii-body-burial-site-a62263

Anon., “Case Closed: Famous Royals Suffered from Hemophilia.” Science Oct. 8, 2009.

Ellis, H, “Jonathan Hutchinson (1828-1913).” J Medical Biography 1993; 1 (1): 11-16.

 Godlee, R., “Sir Jonathan Hutchinson, F.R.S., 1828-1913.” Brit J Ophthalmology 1925; 9 (6): 257-81. 

Ewing, M., “Jonathan Hutchinson FRCS.” Ann Roy Coll Surg 1975; 57: 296-308.

Rogaev, E.I., et al, “Genomic Identification in the Historical Case of the Nicholas II Royal Family.” Proc Nat Acad Science (early edition), 2009; 106 (13): 5258-63. Online at: https://www.pnas.org/content/106/13/5258

                                MEDICINE AT HIGH ALTITUDES

 

         In the late nineteenth century, high-altitude ballooning became popular and adventurous mountain trekkers found ever-higher peaks to conquer. At the extreme elevations participants in both activities encountered difficulties that eventually led to a new specialty: high-altitude medicine. 

         The title, “father” of high-altitude physiology (and of aviation medicine),” is usually awarded to Paul Bert, a French physician and investigator. Another French physician, though, deserves to be included as a “co-father” – Denis Jourdanet. The work of the two might be considered a collaboration between a laboratory investigator, Bert, and a clinically oriented physician, Jourdanet, with Jourdanet supplying the funds.

         Paul Bert (1833-1886) was born in the Burgundy area. He trained as a lawyer but he was intrigued by the mysteries of nature and

Paul Bert (Wikipedia)

eventually took enough courses to sit for a degree. Claude Bernard, one of his examiners, was so impressed with his thesis on respiratory physiology that he took him on as an assistant after he first obtained his medical degree. Bert did experiments on tissue grafting, said to have been helpful to surgeons in the Franco-Prussian War and for which he received a prize from the Academy of Sciences. Bernard got him a professorship at the University of Bordeaux followed by one at the Sorbonne. Bert was politically active, very left-wing, and constantly at odds with the Jesuits. His university appointment was opposed by a group of bishops but, with the influence of Louis Pasteur, he obtained it.

         Denis Jourdanet (1815-1892) was born in the Pyrénée

Denis Jourdanet (Wellcome Library)

mountains and remained there until university age, then studied medicine in Paris. Restless, he shipped off to Mexico before finishing his degree and set up a practice in the Yucatan peninsula. Through the French consul he became well-connected and married the daughter of a wealthy Mexican diplomat. After a return to Paris to obtain his medical degree he moved to Mexico with his wife, who had tuberculosis, and settled, eventually, in Mexico City, where he joined the faculty of the medical school. His wife improved temporarily at their 2240-meter altitude leading Jourdanet to become interested in the effects of altitude and measure barometric pressures on various mountaintops. His wife succumbed to TB in 1859 and he returned to Paris, where he published on the beneficial effects of higher altitudes and drew attention to the similarity of the symptoms of anemia and those seen after rapid ascent to high altitude.

         He designed low pressure air chambers for treatment of tuberculosis and other illnesses and published a book on his work in 1861. That same year France invaded Mexico and shortly after

Low-pressure chamber used by Jourdanet
for treatments (from La Pression Barométrique, 
Hathi Trust)

installed Maximilian as Emperor. Maximilian asked Jourdanet to be his personal physician but Jourdanet declined (wisely). In 1865 he remarried into another wealthy Mexican family and eventually settled in Paris to conduct research. It was then that he met Paul Bert.

         Bert was aware of Jourdanet’s idea that a deficiency of oxygen was the common factor responsible for the comparable symptoms seen with anemia and high-altitude exertion and wanted to study this using low-pressure chambers. Lacking funds, he advertised openly for money and Jourdanet, now wealthy, answered the call. Meanwhile Jourdanet continued treatment of various diseases with the low-pressure chamber, which he called “aerotherapy.” (He was not the first to use this treatment.) In 1875, he published a large tome, Influence de la Pression de l’Air sur la Vie de l’Homme, a two-volume work with numerous illustrations. Following an extensive historical background, he describes his treatment methods and lays out his ideas on hypoxia as the common problem in anemia and high altitude.

         Paul Bert, grateful for the support of Jourdanet, used both high and low-pressure chambers to establish the critical role of oxygen. He subjected animals and humans, including himself, to low pressure states, then reversed the symptoms with added oxygen.

Concentrations in blood of O2 (bottom) and CO2 (top)
plotted against partial pressures (horizontal)
from Pression Barométrique (Hathi Trust)

Conversely, he deprived the air of oxygen at normal pressures, all the while measuring partial pressures of oxygen and CO₂ in the blood. He was the first to map the hemoglobin disassociation curve, though his version was incomplete, and establish that the partial pressure of oxygen is the determinant factor.

         Bert eventually, in 1878, produced his magnum opus, La Pression Barométrique: Recherches de Physiologie Expérimentale. In it he describes his experimental work and presents a thorough history of high-altitude studies and lore up to 1878. In the introduction he gives full recognition to the help he received from Jourdanet, both financial and scientific. The work did not achieve the praise it deserved at first, allegedly because Bert was involved in several political activities that diverted attention, but in time it was recognized as a master work that has endured.

Bert's lab at the Sorbonne. Presure chambers on right wall, air pump in center
(from Regnard, P, La Cure d'Altitude, Hathi Trust)

         Bert was indeed involved in political activities. He was especially forceful in promoting free, secular, and obligatory education with no church involvement. He wrote a science textbook for use in schools. He became a member of the Chamber of Deputies and eventually Minister of Public Instruction. Finally, he was sent to Hanoi to become Governor General of French Indochina, where he liberalized the French rule and reduced the role of the military in governance. Sadly, after only five months in office, his life and career ended with a bout of severe dysentery.

         Many investigators subsequently refined the relation of oxygen to hemoglobin, determined that oxygen diffused into blood and was not secreted (the latter a position held by J. S. Haldane), and worked out the physiology of high-altitude pulmonary edema and acute and chronic mountain sickness. The benefits continue to flow to mountaineers, pilots, and intensive care units. 

 

SOURCES:

West, John B., High Life: A History of High-Altitude Physiology and Medicine. 1998, Oxford Univ. Press.

Olmstead, J. M. D., “Father of Aviation Medicine." 1952; Scientific American, 186 (1): 66-73.

West, John B. and Richalet, Jean-Paul, “Denis Jourdanet (1815-1892) and the Early Recognition of the Role of Hypoxia at High Altitude.” 2013; Am J Physiol Cell Mol Physiol 305: L333-L340.

 

         

         

     

   

         

         

 

TWO DOCTORS WITH ACROMEGALY

 

                Dr. Leonard Portal Mark, born in 1855, son of the British Consul in Marseille, enjoyed an uneventful childhood, studied medicine, and entered practice in London. He was also draughtsman in the St. Bartholomew Hospital Pathology Department (medical illustrator). At age 24 he noted a stuffed feeling in the left ear, followed by pain in the left face, sensitivity to light in his eyes, frequent runny nose, fatigue, and frequent headaches. Eventually he noted enlargement of glove, shoe, and hat sizes, protuberance of his jaw and lower lip, and problems with chewing his food. Amazingly, he failed to see that anything serious was wrong until one day, 25-6 years after his symptoms started, he suddenly realized that he must have acromegaly. For years, he admitted, looking in the mirror every day, “there was a typical acromegalic literally staring me in the face.”

Leonard Mark, ages 24 and 57 (from Acromegaly:A Personal Experience)

Yet, he failed to see the diagnosis. Consulting his St. Bartholomew Hospital colleague, Archibald Garrod (a pioneer in inherited diseases of metabolism and discoverer of alkaptonuria), Mark discovered that Garrod and other physician friends, even his brother and his dentist, knew the diagnosis and assumed that he was aware of it. They had simply avoided discussing an unpleasant topic with him.

          Seven years later, at the age of 57 (1912), Dr. Mark published a memoir recounting his symptoms. He wrote that “I felt some resentment having been kept in the dark for so many years.” But this feeling passed away and soon, “I realized that my friends had acted for the best.” He felt that in some ways he had benefitted psychologically from not knowing that he had a serious malady.

          Pierre Marie, a student and colleague of Charcot, whose name

Pierre Marie (Wikipedia)

is most often connected with Charcot-Marie-Tooth disease, a form of muscular dystrophy, described, in 1886, 2 cases with typical features, naming the syndrome “acromegaly” (enlarged extremity). He distinguished it from myxedema and Paget’s disease. Previous similar cases were pulled from the literature and, the following year, Oskar Minkowski noted an association of acromegaly with enlargement of the sella turcica and, perceptively, suggested that giantism might be another form of the same disease process. Dr. Mark’s symptoms, then, began

One of Pierre Marie's 2 cases (Rev Med)

 

before Marie’s report, but the medical world was aware of it soon after. Mark lived to the age of 75, though it was probably not a comfortable life.

         The Latin word pituita means phlegm. Galen believed that the pituitary was a structure that funneled waste products from the brain to the nose in the form of phlegm. Though other possible functions of the gland were subsequently discussed, no real progress was made (primarily because of its inaccessibility) until the reports of Marie and Minkowski.

         Leonard Mark’s autobiography made it across the Atlantic in an ironic way. William Coley, a talented young surgeon at New York Hospital, was consulted in 1890 by a 17-year-old woman, Bessie

William Coley (Nat Library Medicine)

Daschiell, seeking help for a non-healing injury to her right hand. Coley biopsied the swelling, revealing a “round cell sarcoma” of the bone. Bessie underwent an amputation of her right arm below the elbow but succumbed to metastatic disease 2 ½ months later. The incident deeply affected Coley himself and Daschiell’s closest friend, John D. Rockefeller Jr., who considered Daschiell his “adopted sister” (she was the sister of a close school friend).

     Coley, now driven to study sarcomas, found in the hospital records a case of a German immigrant whose large bone sarcoma, incompletely resected from the neck, had disappeared after a serious bout of erysipelas (a streptococcal infection). Coley tracked the man down and found him, amazingly, to be tumor-free and healthy, 6 years after the surgery. Coley treated future sarcoma patients by infecting them with streptococci, later with injections of fluid from cultured combinations of bacteria, usually streptococci and Serratia marscescens. A significant minority improved or were cured, as were occasional non-sarcoma patients. However, because radiotherapy became popular and the side effects of the vaccine treatment could be severe, his treatment languished. His methods were opposed particularly by James Ewing, a prominent pathologist at Cornell University Medical College, where Coley worked.

     Rockefeller, also stunned by Daschiell’s rapid death, saw the need to fight cancer and provided major funding for a new Memorial Hospital near the Cornell site that eventually became the Memorial Sloan-Kettering Cancer Center of today. He remained friends with Coley.

     A number of years later, when Coley was 51 years old (1913) and vaguely aware of enlarging hands and feet, a friend gave him a copy of Leonard Mark’s autobiography. The friend had received it from an anonymous source, apparently an attempt to discredit Coley. Coley read it in detail. It is unclear whether he already suspected that he had acromegaly, but after reading the book he certainly realized it. He downsized his practice. He apparently did not undergo pituitary surgery but left instructions for his brain to go to his friend, Harvey Cushing, for study. He also suffered from bleeding ulcers and in his seventies died of bowel gangrene from previous adhesions.

Only in modern times has interest in what is now called “immunotherapy” of cancer been revived. Coley is frequently cited as the father of this approach. The plethora of cytokines, including “tumor necrosis factor,” uncovered in recent years has reopened the field on a much more scientific basis.

         Coley never met Leonard Mark, but he must have been deeply impressed reading the story of a colleague on the other side of the ocean who, possibly like himself, took time to appreciate the significance of the slow changes in his physiognomy.

 

 

SOURCES:

Mark, L P, Acromegaly: A Personal Experience. Balliere, London, 1912.

Aron, D C, “The Path to the Soul: Harvey Cushing and Surgery on the Pituitary and its Environs in 1916.” Perspect Biol Med 1994; 37 (4): 551-65.

Kaplan, S A, “The Pituitary Gland: A Brief History.” Pituitary 2007; 10: 323-25.

Marie, P, “Sur Deux Cas d’Acromégalie.” Revue de Médecine 1886; 6: 297-333.

Cohen, H, “Pierre Marie 1853-1940.” Proc Royal Soc Med 1953; 46: 1047-1054.

Hall, S S. A Commotion in the Blood: Life Death, and the Immune System. 1997; Henry Holt & Co.

 

    

 A SPECIAL NOBEL PRIZE

         

         There is a story that the 1930 winner of the Nobel Prize in medicine and physiology first learned of his award from a Swedish journalist. After hearing the journalist, he asked what the prize was for. That was not false modesty; it was because the recipient, Karl Landsteiner, had made so many discoveries that he had to speculate on the winning one. The prize was, in fact, for the determination of the blood groups, a breakthrough that made possible the whole field of transfusions. True or not, the anecdote illustrates the wide range of Landsteiner’s achievements.

Landsteiner was born into a Jewish family in Vienna in 1868. His father, a prominent journalist, died when Karl was six. His

Karl Landsteiner (Wikipedia)

mother saw him through a gymnasium (university prep school) education, after which he entered the University of Vienna Medical School at age 17, graduating in 1891. Interested in biochemistry, he spent 5 years with prominent chemists, including Emil Fischer, and soon after learned bacteriology as assistant to Anton Weichselbaum, who had discovered the meningococcus as a cause of meningitis. He continued to work in Vienna until 1919, rising to Professor of Pathologic Anatomy at the University of Vienna and director of laboratories at the Wilhelmina Hospital. During this time his scientific output was prodigious.

In the infectious diseases, he and Ernest Finger (chief of Dermatology and Venereal Diseases) transmitted syphilis to monkeys (though preceded by Metchnikoff and Roux). On his own, Landsteiner discovered the value of dark field illumination in identifying the spirochete and found that extracts of beef heart improved the Wasserman reaction. Both were discoveries widely used. 

In 1908, during a polio epidemic, he and an assistant were the first to transmit the disease to monkeys. Landsteiner, with

 Constantin Levaditi (Wikipedia)

Constantin Levaditi, a Romanian-born scientist, established that the poliovirus was ultrafiltrable and that it was recoverable from the pharynx, salivary glands, tonsils, and in lymph nodes draining the intestines, proving that polio was a systemic infection. Landsteiner found that convalescent serum inactivated the virus and even created a vaccine. The vaccine failed to prevent disease in monkeys, though, and he abandoned the project. Landsteiner also described the pancreatic findings in what later became known as cystic fibrosis.

  

 Busts mounted in Polio Hall  of Fame, Warm Springs, GA. Landsteiner is fourth from left, 
Franklin Roosevelt is second from right. (Wikipedia)

     Regarding his Nobel Prize work, Landsteiner was long interested in blood transfusion reactions. Familiar with the phenomena of agglutination and lysis of red blood cells, he mixed serum from different donors with washed red cells. The resultant agglutinations distinguished 3 different blood groups, the fourth one discovered by his assistants soon after. This opened the door to transfusion services, especially after the introduction of the anticoagulant, citric acid. Landsteiner later uncovered other blood antigens and, finally, in 1940, he and Philip Levine discovered the Rh factor, which led to the unraveling of the perplexing problem of jaundice of the newborn. 

Diagram of Blood Groups (Wikipedia)

Landsteiner’s life was not always smooth. His mother died in 1908, a traumatic event for a man so close to her (he kept her death mask on his bedroom wall until his own death). Both he and his mother had converted to Catholicism years earlier, not an unusual practice at the time and possibly seen as an aid to his career. Though a tireless and determined worker, socially he was withdrawn and made few friends. Eight years after the death of his mother, and during WWI, he married the daughter of the verger of a Greek Orthodox Church, Helene Wlasto, who agreed to give up her Orthodox connection. A year later, 1917, a son, Ernest Karl, was born.

World War One was hard on Austria. Vienna’s glittering fin-de siècle life had disappeared and its inhabitants were barely surviving. Facilities (and salaries) deteriorated at the University and food was scarce. Landsteiner bought a goat to provide milk for his son as he watched destitute locals, desperate for firewood, cut down trees around his property. To feed his family, he moved to a job as pathologist at a Catholic hospital at The Hague. Despite the heavy workload and poor facilities, he managed to publish 12 papers. His difficulties drifted up to

 Simon Flexner (Wikipedia)

 Simon Flexner at the Rockefeller Institute in New York and, aware of his work, Flexner promptly offered him a position. 

The three Landsteiners started New York life in an apartment above a butcher shop, awakened often by the noise of passing trolleys, though he soon found a small house on Nantucket for quiet weekends. At the Institute, Landsteiner continued his impressive scientific output, concentrating on problems in immunology and serology. His work culminated in the publication of The Specificity of Serological Reactions, a landmark work in a field he had largely pioneered. He considered the work so important that, in another version of the Nobel Prize story, he thought the prize might be for his immunology research. He later collaborated with the chemist, Linus Pauling, on a new edition of his book that was published posthumously by his son, Ernest Karl, a surgeon in Boston. 

Landsteiner’s shyness and aversion to publicity caused him anxiety at the Nobel ceremonies. So much so, that when he was asked to speak at a dinner, Landsteiner deferred to that year's winner of the Prize in literature, Sinclair Lewis, who praised him as “in a thousand cases the master of death.”

Karl Landsteiner worked into his seventies, succumbing to a heart attack in 1943. Cancer took his wife six months later. Peyton Rous, a friend since his arrival in New York, wrote in an obituary appreciation that Landsteiner was “as pure a medical scientist as his material would allow… He believed that facts would make their own way and he left them to do so…” A fitting tribute. 

 

SOURCES:

Bendiner, E. “Karl Landsteiner: Dissector of the Blood.” Hospital Practice March 30, 1991, pp 93-104.

Gottlieb, A M, “Karl Landsteiner, the Melancholy Genius: His Time and His Colleagues.” 1998; Transfusion Medicine Reviews 12 (1): 18-27.

Goldman, A S and Schmalstieg, F C, “Karl Otto Landsteiner (1868-1943). Physician-biochemist-immunologist.” 2019; J Med Biography 27 (2) 67-75.

Bayne-Jones, S, “Dr. Karl Landsteiner: Nobel Prize Laureate in Medicine, 1930.” 1931; Science 73 (1901): 599-604.

Rous, P. “Karl Landsteiner.” In “Obituary Notices: Fellows of the Royal Society.” 1947; Proceedings of the Royal Society 5: 295-324.

Paul, J R, A History of Poliomyelitis. Chapter 11. 1971, Yale University Press.