Section F

A Bit of Medical History

Table of Contents

The Story Of The Medical Student Who Deserved (But Never Got) The Nobel Prize

[On ward rounds in the ICU]

"Nineteen twenty-two," I said. "Insulin therapy was introduced into clinical medicine in nineteen twenty-two."

"Oh well," said the house officer Bill Sedgwick, suggesting by his tone that it really didn't matter whether it was 1922 or 1955. "The first patient to receive insulin was a thirteen-year-old diabetic boy named Leonard Thompson. In what city?" I asked. If the house staff didn't know the date they also would not know the location of this medical milestone, but I was having fun and they didn't seem to mind.

"Boston," guessed Dr. Sedgwick.


"New York," said Dr. Miles.

"London?" said one of the nurses, in a final desperate stab.

"No. Everyone give up?"

All did.

"Toronto. The Toronto General Hospital. January eleventh, nineteen twenty-two. And who received a Nobel Prize for the discovery of insulin?"

"Banting," said Dr. Sedgwick, who was still out to win the trivia prize.

"You're half right," I said. "Banting who?"

"That's his last name. I don't remember his first name."

"Did anybody else get the Nobel Prize for work on insulin?"

No answer.

"How about Best? Banting and Best, does that ring a bell?" The two names, of course, are forever linked with the discovery of insulin. Even many grade school students have heard of Banting and Best.

"That's right," said Dr. Sedgwick. "Banting and Best. I remember now."

"Yes," said Dr. Mance. "I remember too. Banting and Best, but I don't remember their first names or anything about them."

"Actually, they are names you probably heard before you entered medical school. Like Salk and Sabin. Probably because of the Nobel Prize, I bet. Salk and Sabin got the Nobel Prize for the polio vaccine, and Banting and Best got it for insulin. Right?"

There was general murmur of agreement.

"Does anyone disagree?" If my questions seemed obnoxious no one complained. In any case I felt compelled to continue, especially since no one had disagreed with my purposely erroneous statement about Salk, Sabin, and Best.

"Well, for starters, Sabin and Salk did not win the Nobel Prize."

"No? Sure they did," said Dr. Sedgwick. "That can't be."

"Sure they didn't. They developed and introduced the polio vaccines but never got a Nobel Prize for their work. The Prize was given for earlier work on culturing the polio virus in monkey kidney cells, work that was published in 1949. So who got the Prize for work on polio?"

Now they were baffled. I was asking a bit of trivia they must have missed in school. No one answered so I continued.

"The Nobel Prize was awarded to three Americans, Drs. Enders, Robbins, and Weller, in nineteen fifty-four, before the polio vaccine was even released. They were the ones who developed a method to culture the polio virus. Without their work there would have been no vaccine."


"Really. And it was in Boston, too."

"Are you sure Salk and Sabin never got the Nobel Prize?" asked Dr. Sedgwick, still unbelieving.

"I'm sure. They got just about every other prize, but not the one from Stockholm.

"What about Banting and Best? Didn't they get it for discovering insulin?"

"Yes and no. That's an interesting story," I said. "Anybody want to hear it?"

I wasn't sure anyone did, but I wanted to tell it. It is one of the more fascinating stories of medical discovery.

"Yes," said one of the nurses. "Tell us."

"Right," agreed Dr. Mance.

Sensing a trace of sarcasm, I suddenly felt a need to defend the subject of medical history. Looking toward the patient [a young woman recovering quickly from diabetic ketoacidosis] I said, "There's more to a case like this than just glucose and bicarbonate levels. Sometimes we take these modern miracles too much for granted. Since you insist, I'll tell you about the discovery of insulin." And I did.

* * *

Before 1922 young diabetics were treated with low-carbohydrate, starvation diets. Even so, patients with DKA invariably died in coma. William Osler, in his 1892 The Principles and Practice of Medicine, a standard textbook of the era, wrote:

In children the disease [diabetes] is rapidly progressive, and may prove fatal in a few a general rule, the older the patient at the time of onset the slower the course...In true diabetes instances of cure are rare...Our injunctions today are those of Sydenham [an earlier physician]: `Let the patient eat food of easy digestion, such as veal, mutton, and the like, and abstain from all sorts of fruit and garden stuff.' The carbohydrates in the food should be reduced to a minimum.

Reflecting medical practice of the day, Osler's text devotes almost a full page to specific dietary recommendations, listing those items which the diabetic may take and those which were prohibited. Among the latter was "ordinary bread of all sorts."

Osler's comment on "Medicinal treatment" of diabetes was an understatement:

This is most unsatisfactory, and no one drug appears to have a directly curative influence.

In fact, no drug was even indirectly curative. On the subject of diabetic coma, Osler wrote:

The coma is an almost hopeless complication.

Frederick Banting was a 30-year-old surgeon from London, Ontario who had the idea of isolating the specific secretion of the pancreas that lowers glucose in the blood. By the end of World War I scientists knew some substance in the pancreas acted to lower glucose, but no one had been able to isolate it or use pancreatic extract successfully in diabetic patients. Banting moved to Toronto in 1921 to work in the lab of Dr. John Macleod, a Scottish physiologist who was an expert in the field of carbohydrate metabolism.

Banting was aided in his work by Charles Best, a 22-year-old medical student. The two of them succeeded in preparing an extract of pancreas that did lower blood sugar in dogs. This extract, of course, contained insulin. Under their direction the first human trial of insulin took place in January 1922. (History records earlier animal trials of crude pancreatic extract, most notably by a Georg Ludwig Zuelzer in Berlin, but nothing came of that research.)

Leonard Thompson weighed only 64 pounds when he was admitted to Toronto General in December, 1921. His diagnosis: diabetic ketoacidosis. He was initially given a diet consisting of only vegetables [see "A Case of Diabetes Mellitus," New England Journal of Medicine, February 11, 1982]. Before he received insulin Thompson's blood sugar ranged from 350 to 560 milligrams/deciliter.

Thompson was still in the hospital when Banting and Best were ready with their extract in January 1922, so he was the first human patient to receive it. According to the hospital record, Thompson's blood sugar fell from 470 to 320 milligrams% six hours after the injection.

It took Banting and Best two weeks to get more of the extract and Thompson didn't receive his next injection until January 23. His blood sugar responded by falling each time. Thompson continued to receive insulin and was sent home on May 15, 1922, weighing 67 pounds.

Almost from the very beginning the discovery of insulin sparked controversy. Up until early 1922 Macleod had played no direct role in the discovery. Although he had acted as advisor on a number of the experiments, and Banting and Best used his lab, Macleod was actually out of the country in the summer of 1921 when most of the important dog experiments were accomplished.

The earliest scientific reports listed only Banting and Best as authors. In fact, Banting later wrote that he was discouraged in his work by Macleod, and that Macleod told him that "negative results would be of great physiological value." When it became clear that an important discovery had been made Macleod got involved and orchestrated the production of insulin and further research into its use.

At the time insulin was considered a cure for diabetes so the discovery was quite a sensation. And no wonder. Patients near death were miraculously resurrected after only a few injections of the vital hormone. As expected, the discovery lead to the Nobel Prize for Physiology or Medicine. It was awarded in the fall of 1923 to Banting and . . . Macleod!

Upon hearing of the award Banting was furious. In his view, Macleod had done none of the original work but only impeded his own brilliant research. Banting thought Charles Best should have shared the Nobel Prize.

Since Best was only a student at the time, and did not present any of the research at meetings, as did Banting and Macleod, his role in the discovery was not prominently featured. The Nobel committee was aware of Best (he was co-author on the original papers) but was more impressed by Macleod's senior status and the fact that he presented much of the research at scientific gatherings, one of which was attended by a Nobel committee-man. Also, by intention the Nobel committee wanted to honor only two recipients (it was not until 1945 that three people would share a Nobel Prize in Physiology or Medicine). To the Nobel committee in Sweden Banting and Macleod seemed the logical choices.

Banting tried to correct the injustice by publicly giving half of his award to Best (the total monetary award in 1922 was $24,000). As it turns out another scientist was also overlooked by the Nobel committee, a Toronto biochemist named J.D. Collip. Collip was responsible for purifying insulin far beyond what Banting and Best had achieved with their crude extract. In fact Collip had purified all the injections given the Thompson boy except the first one. After being apprised of Banting's gesture Macleod shared half of his prize money with Collip.

For the next two decades there was bitter (and private) feuding among all four men over priorities and who did what. Banting continued to believe that Macleod had hogged the limelight and deserved no credit for the discovery of insulin. Macleod thought Banting was an ungrateful young doctor who didn't appreciate how much he, the senior professor, had contributed to the discovery. Best, of course, was truly slighted by the Nobel Committee and many contemporaries felt he should have been named a recipient of the Prize.

At least Best's contribution has been fully recognized by history, not to mention the University of Toronto. He outlived everyone in the story, dying in 1978 after a distinguished career as a professor of physiology. Collip also achieved long-lasting recognition for his pioneering work on purifying insulin. Macleod died in 1935, in Scotland. As for Banting, he died in a plane crash in Newfoundland in 1941.

* * *

"Well, that's enough about the discovery of insulin," I said. "Anybody have any questions?"

"What happened to the boy who got the insulin?" asked Dr. Sedgwick.

"Oh, glad you asked that. He lived another thirteen years, dying in nineteen-thirty-five at age twenty-seven, of severe bronchopneumonia. They did an autopsy and found the ravages of diabetes, including a shrunken pancreas."

"Any more questions?" There were none.

"OK," I said, "let's go see the next patient."


And A Nobel Prize That Was Awarded (But Not Deserved)

The 1926 Nobel Prize in Physiology or Medicine was awarded to a Danish Scientist, Johannes A.G. Febiger, for his discovery of an organism causing cancer in mice. Febiger called his discovery spiroptera carcinoma, and it promised further advances that might lead to a cancer cure. After the Prize was awarded Febiger's work could not be duplicated, and it was subsequently discredited. There was no spiroptera carcinoma.



(Answers below)

1. Oxygen was discovered in the year ______________by __________________ in (country) _______________.

2. The first antibiotic used in clinical medicine was ______________________ for which _________________, _____________ and_____________ won the Nobel Prize.

3. The stethoscope was invented in the year _________ by _____________ in (country)_____________.

4. De Motu Cordis, perhaps the most famous medical treatise ever written, first described the physiologic process: ________________________.

5. The author of De Motu Cordis was ________________ who lived in the _____________ century.

6. General anesthesia was first demonstrated to physicians in the year _____________ in the city of ______________ by ____________________________ who was a practicing ________________.

7. Insulin was first used in a human diabetic patient in the year _____________ in the city of _________________.

8. The first medical school-trained woman physician in the United States was ____________________, who graduated from _________________ Medical College in 1849.

9. The first woman to win the Nobel Prize for Physiology or Medicine was ______________________.

10. The 1905 Nobel Prize for Physiology or Medicine was awarded to the discoverer of the tubercle bacillus, _________________, of (country) _________________.


1. 1774; Joseph Priestley; England 2. Penicillin; Chain, Florey, Fleming 3. 1816; Laennec; France 4. Circulation of the blood 5. William Harvey; 17th century 6. 1846; Boston; William T.G. Morton; dentist. 7. 1922; Toronto 8. Elizabeth Blackwell; Geneva (New York) 9. Gerty T. Cori (1947). 10. Robert Koch; Germany.

Historical perspective: An Essay

Look around your hospital. Did it always have a pulmonary function laboratory? An intensive care unit? Facilities for cardiac catheterization? A computerized laboratory? If it is newly built or only a few years old, the answer is probably "yes" to all these questions. But if you work in a hospital built before the 1950s, the answer to all is "no." Since the end of World War II there has been a technologic revolution in patient care. In our daily practice we use machines, prescribe drugs and perform operations inconceivable a few decades ago.

For the most part, diseases that we treat are not new. Certain microorganisms may be newly recognized (e.g., Legionella bacterium and human immunodeficiency virus), and some conditions may be more common than in years past (e.g., lung cancer and myocardial infarction), but the basic disease processes are the same. There have always been patients suffering from cardiac and respiratory failure, pneumonia, lung abscess, shock, sepsis and asthma. How did physicians cope with these patients 200 years ago? A century ago? Fifty, twenty, even ten years ago? Answers to these general questions provide a historical perspective, which can be defined as the viewing of our current situation in light of medical history.

There is sometimes a tendency to think that the way we care for patients is the only way, the best way, the universal way. Not so, of course. By examining how medical problems were managed in the past, we can better appreciate today's medical environment and perhaps glimpse an idea of what practice might be like years hence. Medical care has changed radically over the generations and will surely continue to change in dramatic ways.

To illustrate how medical practice has changed, four case histories are presented; each is from the medical literature and is representative of "state-of-the-art" medical practice for its era.

Case I (Laennec, 1818)

A man, aged 29, caught a severe catarrh from exposure to much cold in the beginning of October, which he neglected....This catarrh, after a few weeks, was followed by spitting of blood for several days and, subsequently, by a continual cough, dyspnoea and emaciation. In the beginning of February he come into hospital. At this time he was evidently in a confirmed consumption--being affected with great emaciation, frequent cough, yellow opaque sputa, dyspnoea, diarrhea....Things continued much in the same way until the 17th, when the supervention of more febrile symptoms indicated a slight peripneumony. On applying the cylinder, it was found that respiration was not at all audible on the anterior and lateral portions of the left side of the chest; while percussion gave a much distincter sound than on the right side; and succussion of the trunk produced the characteristic noise of fluctuation. From these circumstances, being convinced of the existence of both air and pus in the cavity of the pleura, and seeing no other means of alleviating the patient, I proposed the operation of empyema. This however was not performed, as he died the same day.

This case is from one of the earliest "classics" of respiratory medicine, Laennec's Treatise on the Diseases of the Chest, published in 1818. In 1816 Laennec (1781-1826) invented the stethoscope (the "cylinder" in this case report). As reported in Treatise, "I was consulted by a young woman laboring under general symptoms of diseased heart, and in whose case percussion and the application of the hand were of little avail on account of the great degree of fatness." By rolling a sheaf of paper into a cylinder and placing one end over her heart, he found "I could thereby perceive the action of the heart in a manner much more clear and distinct than I had ever been able to do by the immediate application of the ear."

Laennec later replaced the rolled paper with a solid wood cylinder a foot long and two inches in diameter, with a hollow center. "This instrument. . .I commonly designate simply the Cylinder, sometimes the Stethoscope."

From publication of Laennec's Treatise onward, for about 100 years, the stethoscope was the premier tool for diagnosing chest diseases pre-mortem. Not until the introduction of chest radiology in the early 1900s was a better tool available.

At autopsy this patient was found to have tuberculous empyema, which Laennec diagnosed after careful dissection. Without antibiotics, it is unlikely that even "operation of empyema" would have helped. Of course, anesthesia was also unavailable to relieve the pain of surgery.

Laennec was a master diagnostician. He "fixed definitely the clinical picture of the disease [tuberculosis]...having separated it by means of auscultation and his pathological studies from all similar affections of the lungs" (Walsh, 1907). Unfortunately, like all doctors of his era, Laennec could not offer meaningful treatment for tuberculosis. The next case, from half a century later, shows a different approach to tuberculosis (phthisis pulmonalia).

Case II (Mackey, 1869)

Phthisis pulmonalia. Mrs. W.--age 31, who had lost her father and sisters of consumption, consulted me in Dec. 1867. For the last six months had had cough, for the last three had been emaciated, and at this time had the prostration, night sweats, diarrhea, and hectic of the third stage of phthisis; hemoptysis had occurred several times: the expectoration was generally purulent. There were violent pains, especially over left chest, and examination revealed a fine crepitus at apex of left lung. The patient was treated with ordinary medicines, and improved gradually. Opium in the form of an atomized spray was found to be the best medicine for relieving cough, and procuring sleep; tincture of steel and carbolic acid used in the same manner relieved, to a certain extent, the profuse expectoration; and although the case became complicated with a peri-uterine haematocele, in February 1868 she rallied from this also.

It was July 1868 before she could walk as far as my house. Her principal symptoms then were debility, pains in the chest, cough, and copious muco-purulent sputum. At this point she began inhalations of oxygen in the proportion of 6 pints to 60 of air, increasing to 12 pints. She took inhalations at intervals of two days, and then found the above symptoms so relieved as to be able to omit all treatment for a time. She herself attributed great benefit to the gas, and was taking no other special medicine at the time. Since then she has borne fairly well the cares of a large family. She has gained flesh, and though there is still a frequent cough, and sputum, a mucous rale about the left apex (I examined the chest two days ago), the progress of the disease is arrested for a time at least.

Today both Laennec's and Mackey's patients would have a chest x-ray, which would no doubt show abnormalities. Sputum examination and culture would confirm the diagnosis, and both patients would receive anti-tuberculous drugs. But it was only in 1882 that Robert Koch discovered the tuberculous bacillus, in 1895 that Roentgen discovered x-rays, and in the 1940s that the first successful anti-TB drug (streptomycin) became available.

As for oxygen therapy, there is no reason to suppose that the intermittent inhalations this patient received were of any benefit. Oxygen, discovered in 1774 by Joseph Priestley, was employed for medical purposes shortly afterward. Nevertheless, it was not until well into the twentieth century that oxygen therapy was placed on a rational, scientific basis.

For almost the entire nineteenth century, oxygen was prescribed only for intermittent use. The first case report of continuous oxygen therapy was published in 1890 (Blodgett). If Dr. Mackey's patient was indeed hypoxic, oxygen delivered intermittently certainly did not help since the body does not store oxygen. Moreover, tuberculous organisms seem to favor lung regions with a high alveolar partial pressure of oxygen. After this fact became known and before the advent of anti-tuberculous therapy, temporary pneumothorax was in vogue as a treatment for tuberculosis. An even more radical procedure was thoracoplasty, which entailed removal of part of the rib cage to permanently collapse the infected lung. The idea behind both procedures was to make the involved lung airless and so starve the tuberculous organisms from lack of oxygen. Although these techniques often did help, they also caused considerable morbidity; compared to modern day chemo-therapy, lung collapse is primitive treatment.

Case III (Barach, 1927)

A man, aged 50, was sick with fever, cough and prostration of two weeks' duration. He was known to have had bronchiectasis for one year. On admission he was deeply cyanotic, dyspneic, and toxic. The lung signs gave evidence of bronchiectatic cavities and a diffuse bronchopneumonia. He was put in an oxygen tent with a concentration of 40 per cent of oxygen. At the end of seven days he was free from cyanosis, moderately dyspneic, very toxic and stuporous. The tent was removed. Four hours later, he was deeply cyanotic, the hands and face were both blue, he has gasping for breath, he was very restless and he was trying to get out of bed. His pulse had risen from 116 to 152 and the respiratory rate from 36 to 50. From a condition of comparative comfort he had passed into one of acute distress, restlessness and imminent collapse. He was transferred to the oxygen chamber, and in three hours after 40 per cent of oxygen had been established, his condition returned to that point before the removal of the tent.

The modern era of oxygen therapy is often said to have begun with the work of John Scott Haldane, the great English physiologist. Haldane used oxygen therapy for victims of war gas injuries and published a brief paper in 1917 outlining the rationale for use of the gas (Haldane). Case III is from a paper on methods of oxygen treatment by Dr. Alan Barach, another pioneer in the field of oxygen therapy. During the 1920s, Dr. Barach led in the development of oxygen tents for use in treating hypoxemic patients. Note that by this time oxygen was used on a continuous basis, a much more physiologic approach than the nineteenth century's intermittent technique.

Of interest is that no blood gas values were reported in Dr. Barach's case; even in the best hospitals of the era, blood gas measurements were not routinely available. lt would take another 35 years for this test to enter the mainstream of clinical medicine. Today blood gas measurements are routine in cases of severe hypoxemia, and in are themselves being slowly edged out by newer, non-invasive methods of measurement, particularly pulse oximetry.

The first arterial puncture performed on humans was done in 1912, by Hurter, a German physician. In 1919 arterial blood gas analysis was first used as a diagnostic procedure. Employing Hurter's radial artery puncture technique, W.C. Stadie (1919) measured oxygen saturation in patients with pneumonia. Stadie was able to show that cyanosis seen in his critically ill patients resulted from incomplete oxygenation of hemoglobin.

Measurement of PO2 and partial pressure of carbon dioxide (PCO2) proved to be more difficult than measurement of the oxygen saturation. lt was not until the introduction of Clark's platinum electrode in 1953 that direct PO2 measurement became routinely feasible (Clark, 1953). Later a PCO2 electrode was developed, and by the 1960s blood gas electrodes were commercially available.

Finally, it is of interest that Barach's patient did not receive artificial ventilation it was also not available in 1927. Even though the oxygen tent relieved the patient's cyanosis, he remained "moderately dyspneic, very toxic and stuperous." The outcome is not reported.

Case IV (Louria, 1959)

A.Z. A 21 year old woman was admitted on Nov. 8, 1957, because of profound respiratory distress. Three days prior to admission she had developed a sore throat, myalgia, bifrontal headache, a dry cough and fever to 103F (oral). She was seen by a physician who noted no respiratory distress or abnormalities on physical examination of the chest. The night prior to admission she developed pleuritic right chest pain, tachypnea and dyspnea. On the morning of admission her respiratory distress became increasingly severe. When seen by her physician she was markedly cyanotic and audible bubbling sounds could be heard at considerable distance from the patient.

Physical examination on admission revealed a critically ill, anxious dyspneic woman who was intensely cyanotic. Her temperature was 40.3 C, respiratory rate 60 per minute, pulse 160 per minute, and blood pressure 130/70 mm Hg...Crackling inspiratory rales and harsh breath sounds were noted throughout both lung fields. Expiration was labored and appeared to be obstructed. There was evidence of consolidation of both lower lobes...Initial laboratory studies showed the white blood cell count to be 2,000 cells per cu. mm. with 58 per cent lymphocytes, 8 per cent monocytes, 7 per cent polymorphonuclear cells, 9 per cent band forms, 13 per cent metamyelocytes, and 5 per cent myelocytes...The patient's arterial oxy-hemoglobin saturation was reduced to 71.1 per cent. Sputum was grossly bloody and contained large numbers of gram- positive cocci. Hemolytic Staphylococcus aureus was grown in pure culture from the sputum. This organism was sensitive to erythromycin, chloromycetin, streptomycin and novobiocin, but resistant to penicillin and the tetracyclines. The Asian strain of influenza A virus was recovered from throat washings. The admission chest roentgenogram revealed dense bilateral lower lobe infiltrates with scattered nodular densities present in the central areas of both lung fields.

The patient was given oxygen through a positive pressure oxygen mask, and administration of erythromycin, dihydrostreptomycin and chloromycetin, 2 Gm. each day, were started. Hydrocortisone, 100 mg. every 12 hours, was injected intravenously, and prednisone, 100 mg. daily, was given by mouth.

Over the first four days in the hospital the patient showed moderate improvement. Oxyhemoglobin saturation rose to 93.9 per cent with use of the IPPB mask...Nevertheless, signs of consolidation persisted, and she remained cyanotic and tachypneic when oxygen therapy was discontinued.

On the fifth hospital day the patient developed high tracheal obstruction which required tracheotomy and vigorous sectioning. Following this episode her condition worsened rapidly...A marked respiratory acidosis developed with the arterial PCO2 rising to 78 mm Hg. The administration of acetazolamide, 1.0 Gm. daily, was associated with the return of arterial blood PCO2 and pH to normal, but there was no improvement in the patient's clinical course. The onset of bloody diarrhea was associated with the recovery of hemolytic Staphylococcus aureus from stool cultures. On the sixth hospital day blood pressure fell to shock levels and the patient died.

Case IV is from a paper on the influenza pandemic of 1957-1958; by that time procedures for measuring blood gases were available in some hospitals. However, it is noteworthy that no mention of artificial ventilation is made in this case report. Today both Cases III and IV would undoubtedly receive artificial ventilation during their hospital courses.

When did artificial ventilation come about? According to Comroe (1977), artificial ventilation was used in laboratory animals for centuries, with one report dating to 1667. By the 19th century, artificial ventilation was commonly employed in laboratory experiments. Despite the laboratory experience, artificial ventilation was not used when clearly indicated, such as in patients undergoing thoracic surgery in whom pneumo-thorax is always a major problem (pneumothorax is preventable with positive pressure insufflation of the lungs).

One factor holding back use of the technique of artificial ventilation was the use of negative pressure rooms for thoracic surgery. In 1904, the influential German surgeon Ernest Ferdinand Sauerbruch published his method of operating on a patient whose body, except for the head, was enclosed in a room kept at slightly negative air pressure; the surgeon and his assistants were also in the negative pressure room (Comroe, 1977). With this technique, the nonoperated lung stayed inflated throughout surgery, but the patient still breathed on his own (albeit under anesthesia), so there was no real artificial ventilation.

Because Sauerbruch's technique was inherently cumbersome, positive insufflation through an endotracheal tube gradually took over. This transition was aided by development of new technology, such as closed circuit anesthesia apparatus (Jackson, 1927) .

Artificial ventilation outside of the operating room took a longer time to develop. Before World War II, artificial ventilators were usually negative pressure machines, best exemplified by the iron lung (Drinker and Shaw, 1929; Drinker and McKhann, 1929). An iron lung surrounds the patient's body except for the head, and alternates a negative atmospheric pressure with the ambient one, resulting in rhythmic expansion of the chest cage (and thus inhalation) in response to the negative extra thoracic pressure. During periods of ambient extrathoracic pressure, the lungs deflate. This type of machine is rarely used today.

A cuirass negative pressure respirator is designed to surround only a portion of the body, either the chest alone or the chest and abdomen together. For a while cuirass respirators were in vogue as an alternative to iron lungs (Collier and Affeldt, 1954). Today cuirass respirators are used occasionally for patients with neuromuscular problems who need artificial ventilation at home. Unfortunately, the cuirass respirator is often difficult to fit precisely to the patient. Also, it is not helpful in patients with significant lung or airway disease, a population for whom positive pressure ventilation is much more beneficial.

Positive pressure artificial ventilation was gradually phased in after World War II, receiving great impetus during the 1953 Scandinavian polio epidemic when there were not enough iron lungs to go around; more than any other single event, this epidemic of paralytic polio demonstrated that positive pressure was easy to implement and every bit as effective, if not more so, than negative pressure ventilation. Even so, positive pressure ventilators were mostly confined to the operating room during the 1950s. With the development throughout the 1960s of intensive care units, mechanical positive pressure ventilation became a widely accepted technique. Today it is a standard therapy for severe respiratory failure in all hospitals.

* * *

A paradox of modern medicine is that we know so much more than in years past and yet we practice in a way that often seems primitive against the forces of nature. Metastatic cancer, shock, brain hemorrhage, pneumonia in the immunocompromised patient these and other conditions often pursue an inexorable downhill course no matter what we do. Yet consider medical practice without anesthetics, x-rays, or antibiotics a primitive state, no doubt. But these three advances only came to us in 1846, 1895, and the 1940s, respectively. What of medicine before then?

More to the point, what will our current practice look like 50, 100, or 150 years from now? Equally as backward as nineteenth century practice appears to us? Probably so. Barring some global catastrophe, there is no reason to doubt that our present state is anything but a transient phase in the continuing progress of medicine.


Barach, AL. Acute disturbance of lung function in pneumonia: methods of oxygen treatment. JAMA 89:1865,1927.

Blodgett, AN. The continuous inhalation of oxygen in cases of pneumonia otherwise fatal and in other disease. Boston Med Surg J 21:481,1890.

Clark, C, Wolf, R, Granger, D, et al. Continuous recording of blood oxygen tensions by polarography. J Appl Physiol 6:189,1953.

Collier R and Affeldt JE. Ventilatory efficiency of the cuirass respirator in totally paralyzed chronic poliomyelitis patients. J Appl Physiol 6:531,1954.

Comroe, JH, Jr. Retrospectroscope. Menlo Park, CA, 1977, Von Gehr Press.

Drinker, PA and McKhann, CF. The iron lung First practical means of respiratory support. JAMA 225:1476,1986.

Drinker, P, and McKhann, CF. The use of a new apparatus for the prolonged administration of artificial respiration. I. A fatal case of poliomyelitis. JAMA 92:1658,1929.

Drinker, P, and Shaw, LA. An apparatus for the prolonged administration of artificial respiration. J Clin Invest 7:229, 1929.

Haldane, JS. The therapeutic administration of oxygen. Brit

Med Jour 1:181,1917.

Jackson, DE. A universal artificial respiration and closed anesthesia machine. J Lab Clin Med 12:998,1927.

Laennec, RTH. A treatise on the diseases of the chest, in which they are described according to their anatomical characters, and their diagnosis established on a new principle by means of acoustick instruments. T. & G. Underwood, London, 1821. (Translated into English by John Forbes; Treatise was originally published in France, in 1818.)

Louria, DB, Blumenfeld, HL, Ellis, JT, et al. Studies on influenza in the pandemic of 1957-58. II. Pulmonary complications of influenza, J Clin Invest 38:213, 1959.

Mackey, E. On the therapeutical value of the inhalation of oxygen gas. Practitioner 2:276,1869.

Stadie, WC. The oxygen of the arterial and venous blood in pneumonia and its relation to cyanosis. I. Exp Med 30:215, 1919.

Walsh, JJ. Makers of modern medicine, New York, 1907, Fordham University Press.


Dittrick Museum of Medical History, Cleveland

Division of Medical Sciences, National Historical Society, Washington, D.C. (part of Smithsonian)

Harvard Museum, Cambridge, MA

Johns Hopkins Museum, Baltimore

Massachusetts Amphitheatre, Cambridge, MA

Mutter Museum, College of Physicians, Philadelphia

National Museum of Health and Medicine, Washington, D.C.

Origin of "Pickwickian Syndrome"

Pickwickian syndrome is the triad of obesity, excessive daytime sleepiness and an elevated level of blood carbon dioxide. To physicians the term "Pickwickian" connotes a fat, sleepy patient with difficulty breathing. The name comes not from any doctor or patient named Pickwick, but is instead traced to a character in Charles Dickens' first novel, Pickwick Papers, published in 1837. At the end of Chapter 53 Dickens introduces a scene involving the fat boy Joe:

A most violent and startling knocking was heard at the door; it was not an ordinary double knock, but a constant and uninterrupted succession of the loudest single raps, as if the knocker were endowed with the perpetual motion, or the person outside had forgotten to leave off...

The object that presented itself to the eyes of the astonished clerk, was a boy - a wonderfully fat boy - habited as a serving lad, standing upright on the mat, with his eyes closed as if in sleep. He had never seen such a fat boy, in or out of a travelling caravan; and this, coupled with the calmness and repose of his appearance, so very different from what was reasonably to have been expected in the inflicter of such knock, smote him with wonder.

"What's the matter?" inquired the clerk.

The extraordinary boy replied not a word; but he nodded once, and seemed, to the clerk's imagination, to snore feebly.

"Where do you come from?" inquired the clerk.

The boy made no sign. He breathed heavily, but in all other respects was motionless.

The clerk repeated the question thrice, and receiving no answer, prepared to shut the door, when the boy suddenly opened his eyes, winked several times, sneezed once, and raised his hand as if to repeat the knocking. Finding the door open, he stared about him with astonishment, and at length fixed his eyes on Mr. Lowten's face.

"What the devil do you knock in that way for?" inquired the clerk, angrily.

"Which way?" said the boy, in a slow and sleepy voice.

"Why, like forty hackney-coachmen," replied the clerk.

"Because master said, I wasn't to leave off knocking till they opened the door, for fear I should go to sleep," said the boy.

Dickens's portrayal lay dormant medically for 119 years, until 1956 when Dr. C.S. Burwell and colleagues published a medical case report titled "Extreme Obesity Associated With Alveolar Hypoventilation a Pickwickian Syndrome."(Amer Jour Med 1956;21:811). After quoting Dickens's description of the fat boy the authors went on to describe their patient, a 51-year-old business executive who stood 5 feet 5 inches and weighed over 260 pounds:

[He] entered the hospital because of obesity, fatigue and somnolence...The patient was accustomed to eating well but did not gain weight progressively until about one year before admission...As the patient gained weight his symptoms appeared and became worse..he had often fallen asleep while carrying on his daily routine...on several occasions he suffered brief episodes of syncope [fainting]. Persistent edema of the ankles developed... Finally an experience which indicated the severity of his disability led him to seek hospital care. The patient was accustomed to playing poker once a week and on this crucial occasion he was dealt a hand of three aces and two kings. According to Hoyle this hand is called a "full house." Because he had dropped off to sleep he failed to take advantage of this opportunity. [Italics original]. A few days later he

...Therapy consisted chiefly of enforced weight reduction by means of an 800-calory diet. On this regimen the patient's weight fell from 121.4 to 103.6 kg [267 to 228 pounds] in a period of three weeks. As he lost weight his somnolence, twitching, periodic respiration, dyspnea and edema gradually subsided and his physical condition became essentially normal.

Since that first medical paper tens of thousands of patients have been diagnosed with sleep disorders. The spectrum of problems ranges from occasional insomnia to sleep walking to the far more serious and potentially life-threatening Pickwickian syndrome. Today virtually all teaching hospitals run sleep labs, where patients with suspected sleep problems can spend one or two nights.

In the sleep lab patients try to sleep while hooked up to several monitoring devices that measure (among other things): air flow through the nose, oxygen saturation, heart rate, chest wall movement, eye movement and the EEG. While you don't need a sleep study to diagnose Pickwickian syndrome, you do need the study to diagnose with certainty that a disorder exists, to characterize its type, and to treat it. Methods of treating the most common disorder, which is obstructive sleep apnea, aren't effective for the less common type, central sleep apnea.


Ondine's curse refers to a condition where the lungs and chest bellows are normal but patients stop breathing, usually during sleep; the sleep apnea is of central and not obstructive origin. The name is applied to patients in whom there is failure of automatic control of ventilation; it implies a defect in that part of the brainstem (medulla) that controls ventilation. Like Pickwickian syndrome, Ondine's curse does not refer to a specific disease but is merely a descriptive term used for certain patients, usually those who have life-threatening central sleep apnea.

But the name? It comes from a legend about an ondine or water nymph. This ondine married a mortal man with the understanding that he would never marry a mortal woman. However, when the ondine later returned to the sea, her husband did remarry. His punishment for this act has varied according to different accounts of the legend, but always seemed to include loss of breathing control (Comroe, JH, Jr. Frankenstein, Pickwick, and Ondine. Amer Rev Respir Dis 111:689, 1975; Sugar O. In search of Ondine's curse, JAMA 240:236. 1978).

The play Ondine, by Jean Giraudoux, published in 1939, seems to be the basis for naming the medical syndrome. In Giraudoux's play the husband, Hans, explains to ondine about hard it is to live with his curse: "A single moment of inattention, and I forget to breathe. He died, they will say, because it was a nuisance to breathe. . ."


X-RAYS (Roentgen, 1901)



INSULIN (Banting, Macleod, 1923)

EKG (Einthoven, 1924)

BLOOD GROUPS (Landsteiner, 1930)

PENICILLIN (Chain, Fleming, Florey, 1945)

CORTICOSTEROIDS (Hench, Kendall, Reichstein, 1950)


POLIO VIRUS (Enders, Robbins, Weller, 1954)

CARDIAC CATHETERIZATION (Cournand, Forssman, Richards, 1956)


CAT SCANS (Hounsfield, Cormack, 1979)

PROPRANOLOL AND CIMETIDINE (Hitchings, Elion, Black, 1988)


Anton Leuwenhoek - Microscope

William Harvey - Circulation of the blood

William Withering - Digoxin

Rene Laennec - Stethoscope

William T.G. Morton, Horace Wells and Charles Jackson - Ether anesthesia

Walter Reed - Transmission of yellow fever

Ignac Semmelweis and Oliver Wendell Holmes - Transmission of puerperal fever

Louis Pasteur - Inoculation for rabies

Rudolph Virchow - Aspects of cellular pathology

Joseph Lister - Antisepsis

Hermann von Helmholtz - Ophthalmoscope

Edward Jenner - Preventive inoculation



PSYCHOANALYSIS (development)

POLIO VACCINE (creation and implementation)

ISONIAZID (discovery)




AIDS VIRUS (discovery)

MRI SCANNING (invention)


HEMODIALYSIS (invention)


HEPATITIS VACCINES (creation and implementation)






Behind every Nobel Laureate is, often, an interesting story of more than just bench research and academic achievement. Alexis Carrel (1873-1944) is a good example. A native-born Frenchman who emigrated to the U.S. in 1904, Carrel became the first person working in an American lab to win the Nobel Prize in Medicine or Physiology. The New York Times ran the following headline on October 10, 1912:






Keeps Heart Beating in Jars and Grafts

the Quick and the Dead

The prize was awarded for "his work on vascular suture and the transplantation of blood vessels and organs." Carrel pioneered anastomosis of blood vessels without injuring their lining. Prior to Carrel, suturing blood vessels meant inviting thrombosis and a poor surgical outcome. His early enthusiasm for vascular repair did not find acceptance in France. Feeling his academic future stifled, in 1904 Carrel moved to North America, first to Canada, then to Chicago. In 1906 he left Chicago for New York City's Rockefeller Institute.

Carrel's new technique involved, first, taking extreme care to avoid crushing the blood vessels and, second, paring back the ends of the vessels to be anastomosed like the cuffs on a sleeve. By suturing the two cuffs together in a special way (called "triangulation") with a very light silk thread (much lighter than routinely used at the time), and adhering to the strictest antiseptic technique, he routinely achieved anastomoses where others had failed.

Because he also kept a culture of heart tissue living indefinitely, the newspapers played up that fact in tabloid fashion. Carrel had also learned to preserve blood vessels in cold storage in a special saline solution, for later reimplan-tation. According to Comroe (1978), Carrel's 1912 vision for the future of vascular sugery "was incredible". . . during the first re-connection of a severed human limb in 1962 "the vessels, nerves, and bones were successfully reattached using the techniques employed in animals by Carrel..."

After the Nobel Prize Carrel basked in new-found celebrity, at least until World War I interrupted his research. In 1914 he returned to France and the French Army where, under wartime conditions, he pioneered an effective technique for preventing wound sepsis. Unfortunately, while the British and Americans appreciated his efforts, antagonistic French surgeons sneered at his emphasis on bacteriology. Carrel had long feuded with French academic medicine over their slowness in adopting his work; indeed, that was one reason he left the country.

After the war he returned to New York, embittered by what he called "the most terrible years of my life, not because of the War, but because I had to live in an atmosphere of incom-petence, vanity and jealousy which made all efforts useless...I would have been able to save a great number of men. Thanks to French medicine, that was not possible."

Carrel continued research in cell growth and in 1930 was joined by Charles Lindbergh, of Atlantic crossing fame, to work on a blood perfusion pump capable of supporting organs in vitro. They worked together for several years and per-formed hundreds of experiments; they also co-authored The Culture of Organs (1938).

Both Carrel and Lindbergh independent, famous, and of superior intellect were enamored of European fascism. At the time (1930s), belief in a superior race or class of humans was popular among many scientists, writers and philosophers. Carrel even gave speeches about eugenics and natural selection. (Lindbergh was also, in the late 1930s, impressed by Hitler's military resurgence; in 1939 he accepted a decoration from Hitler and praised the German air force as a superior fighting machine. Until Pearl Harbor, he advocated that the U.S. remain neutral in the war.)

Obviously, neither pioneer knew what was to come, and their pre-war beliefs did not carry the horrific implication they do today. But in the hindsight of history we see how brilliant people like Carrel and Lindbergh, who each prospered mightily in a democratic society, can play into the hands of fascism and totalitarianism.

Carrel moved back to France in 1939 and ended up on the side of the pro-German Vichy government, in part because they supported him in establishing an institute for the study of universal human problems (such as nutrition). He was actually apolitical during the war and in declining health he suffered two heart attacks in the early 1940s. After France's liberation in October 1944 there was talk of bringing him to trial as a collaborator. His health gave out first and he died November 5, 1944.


Garrison FH. An Introduction to the History of Medicine, W.B. Saunders Co., 1922; pages 763-4.

Comroe J. Who was Alexis who? Am Rev Resp Dis 1978;118:391-92.

Moseley J. Alexis Carrel, the man unknown. JAMA 1980; 244:1119-21.

Bendiner E. The paradox of Carrel: Science and 'super-science'. Hospital Practice, February 1981;125.

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