FLU SHOTS 100 YEARS AGO

     Just for fun I decided recently to peek at the contents of the JAMA from 100 years ago. As you might expect several articles dealt with medical problems of WWI soldiers and several with the 1918 influenza epidemic, also roaring through the military. What caught my eye, though, was the attention paid to influenza vaccines.

     Influenza was believed by many to be caused by “Pfeiffer’s bacillus”, a small

Richard Pfeiffer (Wikipedia)

fastidious rod now considered to be the bacterium Hemophilus influenzae. However, because Pfeiffer, a protégé of the great bacteriologist Robert Koch, could not produce the illness in animals, and because the bacillus turned up in other conditions and in normal throats, proof of its causative role remained elusive. Brushing aside these uncertainties, however, influenza vaccines hit the market rapidly and were aggressively promoted.

     The power of vaccination was well known by then and several, such as smallpox, rabies, and typhoid, were available. William Park, director of New York City Health Dept’s

William Park (Wikipedia)

laboratories, who had already made diphtheria antitoxin and vaccine, made a three-dose influenza vaccine from Pfeiffer’s bacillus, widely used in the military and by industrial employees. A professor of bacteriology at Tufts Medical School, Timothy Leary (not the marijuana guy), made another one, used in state custodial institutions and on the private market. At the University of Pittsburg Medical School a vaccine was created from 13 different strains of Pfeiffer bacillus (employed by the Red Cross), at Tulane still another, and in New York a private physician, Horace Greeley, made his from a cocktail of 17 strains.

      But was Pfeiffer’s bacillus really the cause of influenza? More studies generated more uncertainty. Pneumococci and streptococci were now turning up in greater numbers in sputum and lung samples than Pfeiffer’s bacillus. Based on this, Edward Rosenow of the Mayo Clinic made a vaccine from five different respiratory tract bacteria, including

Preparing Rosenow vaccine at Chicago Public Health Lab (from A Report on
the Epidemic of Influenza in Chicago, 1918. Courtesy National Library of Medicine)

pneumococci and streptococci. It was distributed to the upper Midwest and manufactured by the City of Chicago, where over 500,000 doses were produced.

     Could all these vaccines be effective? Most reports said they were, but sensible readers realized that was impossible. Study design had been faulty in all but one case,

George McCoy (NIH Almanac)

said William Park of New York and George McCoy of the US Public Health Service in an important article. And that one exception failed to show any protective effect. The missteps, they said, were giving vaccines without randomization, using too few subjects, and starting the studies well after an epidemic begins. Park and McCoy each performed their own studies, Park with employees of the Metropolitan Life Insurance Co. and McCoy with inmates of a “state institution for the insane” in California. Both studies began before the flu hit their subjects, both ensured comparable study and control groups, and both employed the Rosenow vaccine. Neither study showed any protective effect, thus setting important precedents for future vaccine trials. (True randomization and blinding of experimenters were later developments. The first such trial was in 1943, evaluating a remedy for the common cold.)

     That a filterable agent might be the cause of influenza had occurred to only a few people during the pandemic. One was Charles Nicolle, winner of the Nobel Prize for his discovery of the louse as the vector of epidemic typhus. He reported transmission of flu to monkeys and humans with submicroscopic filtrates of sputum from flu sufferers. Eventually he and others with similar ideas were proven to be correct, paving the way for modern flu vaccines.

      

     HAPPY HOLIDAYS TO ALL, AND DON’T FORGET YOUR FLU SHOT!

    

SOURCES:

Eyler, John M. “The State of Science, Microbiology, and Vaccines Circa 1918”. Public Health Reports. 2010 suppl 3; 125: 27-36.

McCoy, G W. “Pitfalls in Determining the Prophylactic or Curative Value of Bacterial Vaccines” Public Health Reports 1919; 34(22): 1193-5.

Sholly, A I and Park, W H. “Report on the Vaccination of 1536 Persons Against Respirtory Diseases, 1919-20.” J Immunology1921; 6: 103-16.

McCoy, G W and Murray, V B. “The Failure of a Bacterial Vaccine as a Prophylactic Against Influenza” 1918; JAMA 71(24):1997.

Nicolle, Charles and Lebailly, Charles. “Recherches Expérimentales sur la Grippe” Annales de l’Institut Pasteur 1919; 33: 395-402.

Bhatt, Arun. “Evolution  of Clinical Research: A History Before and Beyond James Lind” Perspect Clin Res 2010; 1(1): 6-10.

Bike Spokes and a Wrong Turn Advance

Fracture Treatment

by

Roy Meals MD

     Gavriil Ilizarov, a Pole, attended medical school in Crimea and Kazahkstan during World War II and then, without any practical training, was posted to Kurgan, Siberia. This war-torn region was 1200 miles east of Moscow, far away from any established center of advanced understanding. The area was rife with wounded soldiers suffering from nonhealing, infected fractures.

     With vast need, limited resources, and no preconceptions to restrain him, Ilizarov developed an external fixation frame, which would support a tibia fracture, for instance, during healing. As others had done before, he placed pins perpendicular to the bone on both sides of the fracture site and left the pins protruding through the skin.  He then attached the pins to each other with longitudinally aligned threaded rods—the external fixator.

     By 1955, Ilizarov had become chief of trauma and orthopedics at his Siberian outpost. Because resources remained scarce, he used bicycle

Gavril Ilizarov (photo by Dr. Bernd-Dietmar
Parteke, posted on Wikipedia)

spokes for the bone-penetrating pins in his external fixators. The spokes were flimsy compared to the stout quarter-inch-diameter pins previously employed; but when tensioned, the spokes met the need and did so with minimal soft tissue injury. Ilizarov compared the complete construct to that of a bicycle wheel, where the bone was the fully-stabilized hub. The “rims” were metal rings encompassing the limb at several levels above and below the injury site, and the tensioned wires passing from hub to rim (bone to rings) were bicycle spokes. Once the spokes and rings were in place, the rings were secured to one another with the threaded rods.

   The aim of the external fixation was to hold the fractured bone ends firmly against each other. Without any motion at the fracture site, the bone-producing cells, osteoblasts, could begin to bridge the gap. This was problematic, however, when the gap was large, because osteoblasts can “jump” only so far, across a stream but not across a chasm. Ilizarov used a wrench to make daily, tiny adjustments of the rings on the threaded metal rods and could thereby slowly draw the bone ends together and close the gap. He showed the nurses how to perform this at home to close the fracture gap in almost imperceptible increments over weeks.

     One confused nurse, however, kept turning the wrench the wrong way, repeatedly distracting the bone ends rather than drawing them together. To Ilizarov’s surprise when he saw an X-ray of the patient weeks later, the slowly expanding gap was filling in with new bone. The bone-forming cells had been toiling happily, unaware that their task was ever-expanding.

     Other surgeons had lengthened limbs through external distraction but had always filled the gap in the lengthened bone with bone graft taken from elsewhere in the body, typically the pelvic rim. This necessitated additional surgery to harvest the graft and risked the development of donor site pain, disfigurement, and disability. Sometimes the gap in a bone was too big for even the largest possible bone graft to span it.

     In an ah-ha moment Ilizarov realized that by moving the bone ends apart ever so slowly (less than a sixteenth of an inch a day in six evenly spaced intervals), new bone would fill in the gap on its own. (Yank on taffy and it snaps in half. Pull on it gently and it stretches.) This slow movement between bone ends could allow lengthening of bones that had healed too short and also could correct angular and rotational deformities of fractures that had healed with misalignment. (Twist taffy slowly, it twists.) Ilizarov applied the technique widely, and his patients called him “the magician from Kurgan.” Nonetheless, the medical establishment in Moscow considered Ilizarov a quack and discounted his growing achievements and reputation.

     This began to change when Russian high jumper Valeriy Brumel injured his leg in a motorcycle accident in 1965, a year after winning the Olympic gold medal. Following 3 years of multiple and unsuccessful operations in Moscow to heal the injury, Brumel traveled to Kurgan for treatment. He recovered sufficiently to high jump 6 feet 9 inches, which was 7 inches off his world record but still quite respectable for somebody who had been hobbled by injury for years.

     Regardless of his success in treating Brumel, Ilizarov’s contributions did not receive the recognition they deserved. This was even though his center in the 1970s grew to 24 operating rooms, 168 physicians, and around 1000 beds—by far the largest orthopedic center in the world.

     Then in 1980, an Italian adventurer sought Ilizarov’s help after European doctors had given up hope of ever producing a sound leg. The mountaineer had broken his leg 10 years previously and was left with an unhealed fracture with an inch of shortening. After Ilizarov achieved bone healing and lengthening, the grateful patient called Ilizarov “the Michelangelo of Orthopedics.” On return to Europe, the patient’s result astounded the Italian doctors, who then invited Ilizarov to speak at a European fracture conference in 1981. Ilizarov gave three lectures, the first time he had presented his material outside the Soviet Union. At the end he received a 10-minute standing ovation.

                   

     In subsequent years, others have refined Ilizarov’s external fixator hardware and technique. Now many limbs with unhealed fractures, shortening, and angular or rotational deformities have been spared amputation beginning with that one patient who turned the wrench the wrong way. Anybody could do that, but Ilizarov recognized the implications and appreciated that the wrong way might be the right way. 

Sources:

Abdel‐Aal, A. M. (2006). Ilizarov Bone Transport for Massive Tibial Bone Defects. Orthopedics. 29(1):70‐74.

Aronson, J. e. (1989). The histology of distraction osteogenesis using different external fixators. Clinical Orthopaedics and Related Research. 241:106‐116.

Codivilla, A. (1904). On the means of lengthening, in the lower limbs, the muscles and tissues which are shortened through deformity. Am J Orthopedic Surgery, 2:353.

Smith, D N., Harrison. M H M. (1979) The correction of Angular Deformities of Long Bones by Osteotomy‐Osteoclasis. The Journal of Bone and Joint Surgery. 61‐B(4):410-4.

Spiegelberg B, Parratt T, Dheerendra SK, Khan WS, Jennings R, Marsh DR. (2010). "Ilizarov principles of deformity correction". Annals of the Royal College of Surgeons of England. 92 (2): 101–5.

Svetlana Ilizarov (2006). "The Ilizarov Method: History and Scope". In S. Robert Rozbruch and Svetlana Ilizarov. Limb Lengthening and Reconstruction Surgery. Boca Raton, CRC Press.

WESTERN MEDICINE IN SHOGUNATE JAPAN

     The Tokugawa shogunate threw up an invisible wall around Japan, limiting contacts with the western world. The Portuguese had arrived in 1542-3 but, along with the Spanish, had been forced out by 1638, largely due to anxieties over Catholic missionary activity. There had been little exchange of medical ideas. Contact with the Dutch continued, however, since they were Protestant, avoided missionary work, and traded. In 1641 they were ordered to move their trading operations to Dejima, a small, fan-

Diagrammatic sketch of Dejima, with bridge to mainland (Wikipedia)

shaped, closely guarded man-made island in Nagasaki Bay. To care for their own personnel the Dutch East India Company brought physicians to Dejima.

     Japanese medicine at the time was based on traditional Chinese texts, mainly from the T’ang dynasty (618-907), emphasizing herbal remedies along with acupuncture and moxibustion (application of smoldering substance from Artemisia leaves over wet skin). Anatomical knowledge was almost non-existent, surgery was seldom practiced, and diagnosis was based on examination of the pulse, tongue, and patient demeanor.

     The bridge between Dejima and the mainland was the keyhole through which bits and pieces of Dutch medicine trickled into Japan. In the 1650s a barber-surgeon named Caspar Schamberger accompanied the chief of the Dejima station on the obligatory annual journey to Edo (early name for Tokyo), to report to the shogun. The court physicians showed great interest in Schamberger’s medical system and published digests of his teaching. Some of physicians in Dejima were true scholars. Willem Ten Rhijne, for

Willem Ten Rhijne (Wickipedia)

example, arrived 1674. He had studied medicine in Leiden under Franz de la Böe, a promoter of iatrochemistry – a teaching that health and disease were based on body chemistry. Ten Rhijne imparted the new ideas to the few able to hear him, though his greatest contribution was a full description of Japanese medicine, including details of acupuncture. Perhaps the most well known Dejima physician was Englebert Kämpfer (served 1690-2), an adventurous German physician-scholar, famous for his collection of Japanese artifacts and a three-volume

Dutch officers and Kämpfer on journey to shogun's court, from
Kämpfer's history of Japan (Hathi Trust)

history of Japan – the best description of Japan at the time. Curious students and physicians began gravitating to Dejima for instruction.

     Japan changed course under the rule of shogun Tokugawa Yoshimune (ruled 1716-1745). Yoshimune, a reformer,  recognized the importance of western science. He relaxed censorship of foreign books and ordered the teaching of Dutch, setting the stage for Dejima’s straightjacket to loosen. 

     Some years later two Japanese students, Sugita Gempaku and Maeno Ryotaku, obtained a Dutch version of an anatomy text by the German

Sugita Gempaku (Wikipedia)

professor Johann Adam Kulmus (pub’d 1734). To see how accurate the book’s illustrations really were they attended the dissection of an executed criminal, book in hand. In Japan human dissections were limited to the occasional executed criminal. The few that were allowed were performed by the eta, a caste comparable to untouchables in India. Sugita and Maeno saw that the criminal’s internal organs corresponded well to Kulmus’s illustrations (unlike Chinese texts) and they, with companions, laboriously translated the book. The result was the Kaitai Shinso (1774), considered the most important book in the introduction of western medicine to Japan. 

The Kaitai Shinso, 1774. (Hath trust)

Comparable page from Kulmus' anatomy text, latin edition (Hathi Trust)

     The book launched an enthusiasm for the study of western knowledge, known as the Rangaku (“Dutch study”). Twelve private medical schools offering instruction in western medicine and Dutch language opened up in the following years. An illustrated surgical text by Lorenz Heister, a German surgery professor, was translated into Japanese and circulated

Surgical text by Heister (Hathi Trust)

widely. The first Japanese pathology text was published in 1847.

     Dr. Philipp Franz Balthasar von Siebold, a polymath and collector in Dejima, introduced in the 1820s the new methods of auscultation, percussion, and palpation. He also taught techniques of paracentesis, thoracentesis, and modern cataract

von Siebold using telescope (Wikipedia)

surgery. He tried to introduce vaccination but his virus had lost viability.

     Smallpox vaccination was finally brought into Japan by Otto Mohnike, a German physician in Dejima. Vaccination usually traveled to countries far from Europe by sending groups of children on ships and vaccinating one after the other on the voyage to keep the virus alive. But Japan would not admit foreign children. Mohnike, in1849, brought live virus from nearby Batavia (Java), about 50 years after its discovery.

      As the shogun’s authority weakened the pace of change accelerated: a western-oriented medical school opened in Nagasaki where dissection was permitted (1859), six western-trained doctors were appointed as physicians to the shogun (1858), and the first two Japanese students were sent abroad to Holland to study medicine, in 1861. In 1867 the shogunate was overthrown and the Meiji restoration of the monarchy begun. In the 1870s, realizing that Germany led the world in medical teaching and research, medical instruction switched from Dutch to German. German professors were imported and Japanese students dispatched to Germany. A law was passed requiring all physicians to study western medicine, almost putting traditional medicine out of business (though it could still be practiced).

     One more physician, Dr. James Hepburn, deserves mention. A

Dr. James Hepburn (Wikipedia)

Protestant missionary doctor, he set up a clinic in Yokohama, where he taught students. His reputation was made, though, when a famous Kabuki actor returned to the stage after Hepburn had amputated a gangrenous leg and provided him with a prosthesis. Hepburn developed the first comprehensive Japanese-English dictionary and a romanized system of the Japanese language that still bears his name.

     Modernization of medicine in Japan continued at a rapid pace, as did modernization in all the scientific and technical fields. The rest is history.

SOURCES:

Bowers, John Z. When the Twain Meet: The Rise of Western Medicine in Japan. 1980; J Hopkins Univ Press.

Bowers, John Z. Western Medical Pioneers in Japan. 1970; J Hopkins Univ Press.

Bowers, John Z. Medical Education in Japan: From Chinese Medicine to Western Medicine. 1965; Harper & Row, N.Y.

Genpaku Sugita. Dawn of Western Science in Japan. 1969; Hokuseido Press, Tokyo. (Translated by Ryozo Matsumoto)

Historical Anatomies on the Web: Kulmus, at: https://www.nlm.nih.gov/exhibition/historicalanatomies/kulmus_bio.html

MEDICAL HISTORY ON NETFLIX:

Life at the Charité

     I stumbled recently onto a Netflix TV series entitled “Charité”, dealing with one of the most interesting periods in the history of medicine. The scene opens at the famous Charité Hospital in Berlin in 1888, the “year of the three Kaisers” (see the blog of Feb 11, 2017). As far as I can tell it is fairly accurate historically, though a fictional romantic plot is woven into it.

     The story opens in 1888, the year that Kaiser Wilhelm I died and was succeeded by his son Frederick William, already suffering from a laryngeal cancer. Rudolf Virchow, the pathologist who was unable to find malignant cells in the Prince’s laryngeal biopsies, is

Ernst von Bergmann (Wikipedia)

shown discussing the case with Ernst von Bergman, the famous surgeon who had wanted to operate on Frederick. Von Bergman was a pioneer, who had introduced aseptic surgery into Germany early on, developed steam sterilization of instruments, and developed expertise in neurosurgery before it was a recognized specialty. His textbook, Surgical Therapy of Diseases of the Brain, went through three editions and broke new ground.

     It was an exciting time in medicine. Bacteria were accepted as causes of several diseases. In Berlin Robert Koch had seen the

Robert Koch (Wikipedia)

tuberculosis bacillus in 1882, the diphtheria organism was isolated in 1884 by Friedrich Löffler, and the Japanese bacteriologist, Kitasato, isolated the toxin causing tetanus. Paul Ehrlich was improving histological stains and embarking on antiserum studies. In Paris, Elie Metchnikoff had shown the effects of phagocytosis (1884), and Roux and Yersin had demonstrated the diphtheria toxin (1888).

     The principal character in the drama is Emil Behring (later von Behring), an excitable, often

Emil von Behring (Wikipedia)

pugnacious, but intelligent and hardworking scientist. He was an army doctor, assigned as a research assistant to Robert Koch. There, building on Roux and Yersin’s work, he developed a diphtheria antiserum with the help of Ehrlich and others. Diphtheria was a serious problem. Epidemics involving thousands of children swept through Berlin and

Paul Ehrlich (Wikipedia)

other cities, and with a mortality of a little over 50%, numerous families were devastated.

     Not shown in the film is that Behring tried, unsuccessfully, to provide a vaccine against tuberculosis in cattle, a project that squandered time and energy. The rest of the story I won’t divulge here.

     The Charité Hospital, serving as background in this series, has a long history. In the early 1700s a pesthouse for plague victims was erected at the southeast gate of Berlin that, when no plague appeared, became an almshouse for the poor. In 1726 a 200-bed “lazarette” was added to the almshouse, and when it opened as a combination hospital and medical school for military doctors it was baptized the “Charité”. Admissions went from about 600 per year to about 6000 by the end of the century, almost all poor workers. In the 1780s, related to shameful conditions, new buildings replaced the old ones. The miserable conditions for the patients continued, however. One observer noted that the Charité did more for the decimation of its population than the guillotine did in other cities. Patient mortality was about 30% and attendants were so poorly paid that they stole food from patients. Conditions improved somewhat by separating the almshouse function from the hospital, housing the poor nearby.

     In 1795 educational facilities for military doctors were enlarged to accommodate a steadily growing army, the new facility being named the “Pépinière”. In 1810 the University of Berlin and its medical school were founded with the help of Wilhelm von Humboldt, brother of the explorer and polymath Alexander (the university was renamed Humboldt University in 1949). Both medical teaching and research were instituted, a combination that fueled the great discoveries to come. The Charité, considered too shabby for training civilian doctors, was transformed into a more modern facility and its administration transferred from a bureau of poverty to the first Minister of Education in Prussia, Karl von Altenstein. The military built a new Medical-surgical Academy and shared use of the Charité with the University. Medical education in the military was free but required 8 years of service after graduation.      

Die Charité Hospital, 19th Century (Wellcome Library)

     Specialization began in the early 1800s, with the establishment of neuro-psychiatric, pediatric, ophthalmology, and physiology departments, followed by many others. Additional building progressed to accommodate the new activities.

German cartoon of Behring drawing serum from a horse (Wellcome Library)

    In spite of medical and scientific progress the lot of the patients improved only modestly. Rooms were overcrowded and unclean, bathroom facilities rudimentary, and patients often roughly treated by orderlies. Some of this appears in the TV series. Also on the screen are efforts by representatives of the SPD (Socialist Party of Germany, whose activities were suppressed by the government until 1890) to organize a strike in the hospital. Outside the hospital the “Krankenkasse”, the health insurance for lowly paid workers created by Bismark, was threatening a boycott of the hospital and actually carried it out in 1893. The government finally took notice and over the next two decades a major rebuilding took place, finishing in 1917 – during WWI. The prominent military presence in the hospital disappeared after the war, while civilian clinical and research facilities expanded. In the late 1930s Naziism decimated the faculty but after WWII and the reunification of Germany the hospital was rebuilt and modernized significantly.

     Presently the hospital has four modern campuses around Berlin. According to Wikipedia eleven Nobel Prize recipients have been connected with the Charité one way or another. Three are in the TV program: Behring, Koch, and Ehrlich.

SOURCES:

Fischer, Ernst. Die Charité. 2009, Siegler Verlag, München.

Linton, Derek. Emil von Behring: Infectious Disease, Immunology,    

    Serum Therapy. 2005, American Philosophical Society.

Marquardt, Martha. Paul Ehrlich. 1951, Henry Schuman, N.Y.

Brock, Thomas. Robert Koch: A Life in Medicine and 

   Bacteriology. 1999, ASM Press.

Salcman, Michael. “Von Bergmann, Kocher, and Krönlein – A 

   Triumphirate of Pioneers with a Common Neurosurgical   

   Concept”. 2013. Acta Neurochirurgica, 155: 1787.

DANGER IN THE BITTERROOT VALLEY:

EARLY STRUGGLES WITH SPOTTED FEVER

     One of America’s most idyllic spots, the Bitterroot Valley, nestled between two mountain ranges in southwest Montana, seemed a healthy place. Lewis and Clark, passing through the Valley, and native-American peoples living there did not

Bitterroot Valley today (Wikipedia)

manifest unusual illness. After the Civil War settlers moved in, felling thousands of trees in the western side of the Valley to feed a burgeoning lumber industry. Scrub vegetation, populated with small mammals, replaced the trees. By the 1880s scattered cases of a “spotted fever” were reported, usually fatal, most coming from the west side of the Valley, and most showing recent tick bites. Between 1895 and 1902 64 people died out of 88 with the disease.    

     In 1902 two investigators from the University of Minnesota, Louis Wilson and William Chowning, suggested the wood tick as a vector and found organisms in the blood of victims they believed were a type of Pyroplasma, similar to that causing Texas cattle fever, another tick-transmitted disease. The notion of insects transmitting disease was popular. In the previous 25 years mosquito transmission of filaria, malaria, and yellow fever, and tick transmission of Texas cattle fever had all been discovered.

     Getting rid of ticks, though, by burning brush and killing animal hosts didn’t reduce the disease incidence. Other

Howard Ricketts,
martyr to typhus (Wikipedia)

investigators cast doubt on the tick theory, adding confusion, until the arrival of Howard Ricketts and William King. They were able in 1906 to infect guinea pigs and to prove that ticks transmitted the disease. Ricketts also thought he saw tiny microorganisms he believed were the disease agents but could not culture them. Stymied by an interruption of funding, Ricketts left for Mexico to study typhus (another spotted fever). He perished in Mexico, tragically, from that very disease.

     Ricketts had recommended learning more about wood tick habits, enticing Robert Cooley, Montana State entomologist, to step in. Cooley employed Willard King and Clarence Birdseye (who later founded the frozen food industry), both field biologists, to collect ticks and wild animals for study. The work was hazardous. Their lab was set up in an old two-room log cabin in which one man had died of

Cabin and tent of Cooley's team, Bitterroot Valley
(National Library of Medicine)

spotted fever. The yard, full of ticks, was burned, then sprayed with kerosene (a tick repellant), and the team slept in tents around the cabin. As they worked collecting animals and ticks they wore high shoes, with tight kerosene-soaked khaki leggings above them, and doused their outer clothing with kerosene. They stripped and inspected each other for ticks every two hours. Somehow they remained healthy.

     The team demonstrated a 2-year cycle from egg to adult tick and showed that adults fed primarily on large domesticated animals. As a result dipping centers were set up to “de-tick” farm and domestic animals. But, related to poor dipping agents and bureaucratic infighting, the program foundered and spotted fever (now called Rocky Mountain spotted fever) claimed more victims.

     What about the supposed causative agent, Pyroplasma? No one else could find it. S. Burt Wolbach, a young Harvard pathologist, saw tiny intracellular organisms, particularly in vascular endothelial cells, that he could not grow and which he named Dermatocentroxenus rickettsii, in honor of Ricketts (later renamed Rickettsia rickettsii). They were a new type of organism that grew only in cells, the details of which had to await further developments in technology.

     In the era before antibiotics the main strategy against infectious diseases was vaccination, and so it was with the spotted fever.

Roscoe Spencer (National Library
of Medicine)

Roscoe Spencer, a US Public Health Service physician, and Ralph Parker, a Montana entomologist, working in an abandoned two-story brick schoolhouse in Hamilton (in the Valley) in the 1920s, discovered that injecting material into guinea pigs from ground-up infected ticks, sterilized with formalin and phenol, could produce an imperfect but substantial immunity. Spencer developed this into a commercial vaccine.

     Vaccine production was a cumbersome process. Each year’s supply required collection of 30-40,000 adult ticks to feed on 4 to 6,000 rabbits and 20-30,000 guinea pigs. The adult ticks were fed on rabbits, then collected for egg laying. The hatched larvae were fed on newly infected rabbits, dropped off, and molted into nymphs. The nymphs fed on more rabbits (400/rabbit), were

Brick schoolhouse where original vaccine work
was done (National Library of Medicine)

collected, dried with hair dryers, and kept at 22 degrees C to molt into adults. The adults were stored at near freezing levels for 6-12 months (to enhance vaccine efficiency), after which they were warmed up and fed on guinea pigs. Swollen with blood, they were emulsified in a Waring blender with formalin, phenol, and saline. Finally, after storage, further dilution, and purification, the vaccine was ready, and was accepted by residents.

      The toll was heavy. In the process three laboratory workers died of spotted fever. Others, including Spencer, Parker, and a third all developed tularemia, a tick-born disease originally discovered in Tulare County, California (they survived). Spencer, depressed, was transferred back east. The head of the tick-rearing room resigned, and Parker carried on as chief in a new, safer laboratory building.

     The tick-based vaccine continued to be produced by the Rocky Mountain laboratory until 1948 when it was replaced by an egg yolk-derived vaccine and the advent of antibiotics. There is no vaccine available today. The laboratory continues as a part of the National Institute of Allergy and Infectious Diseases/NIH.

     Once considered a localized disease, Rocky Mountain spotted fever has been found throughout much of the U.S., primarily in the central eastern and mid-western states. Its history could be said to have had a “rocky” beginning, with false starts and at least three martyrs.

SOURCES:

Harden, Victoria. Rocky Mountain Spotted Fever: History of a Twentieth Century Disease. 1990; J Hopkins Univ. Press.

Price, Ester. Fighting Spotted Fever in the Rockies. 1948; Naegele Printing Co. Helena.

Ricketts, H. “The Transmission of Rocky Mountain Spotted Fever by the bite of the Wood Tick (Dermacentor occidentalis). 1906; JAMA 47: 358.

Spencer, R and Parker, R. “Rocky Mountain Spotted Fever: Vaccination of Monkeys and Man. 1925; Public Health Reps 41: 2159-67.

Wolbach, S B. “Studies on Rocky Mountain Spotted Fever”. 1919; J Med Research 41:3.

THE FIRST BRAINWAVE RECORDINGS

     When we want to know if someone is “legally dead” we look at the brain waves – the electroencephalogram. This sophisticated diagnostic tool also helps diagnose a wide range of other neurologic problems, especially seizure disorders. The first electroencephalograms (EEGs), however, were performed for another purpose.

     The first to record human brain electrical activity was Hans Berger, a professor of Psychiatry at the University of Jena,

Hans Berger (Wikipedia)

Germany. Berger, born in 1873, was the son of a physician and grandson of a celebrated poet, Friedrich Rüchert. Without finishing university studies he enlisted in the military, after which he decided on a medical career. On receiving his degree he was taken on as assistant to Otto Biswanger, Professor of Psychiatry at Jena, who was working on general paresis (tertiary syphilis of the central nervous system), a common problem in mental hospitals of the time. In the 1890s, though, Berger veered off into other realms: the relation of mind and matter and the conservation of energy in the brain.

     The principle of conservation of energy had been established during the nineteenth century, and some investigators sought to apply these principles to the brain. The Viennese neuropsychiatrist Theodor Meynert, for example, felt that when energy is expended

Theodor Meynert (Wikipedia)

in an area to produce a thought or action, an equivalent energy must be transferred from another part. Meynert and a colleague, Alfred Lehmann, surmised that energy was distributed around through changes in blood flow, regulated from centers deeper in the brain. Brain energy could be in the form of heat, electrical energy, or “psychic” (mental) energy, all derived from chemical (nutritional) sources. 

     These ideas were attractive to Berger. He believed in an interaction between “mind and brain”, as opposed to another school, led by John Hughlings Jackson, a British neurologist, that insisted on a separation between brain physiology and psychologic processes. Berger's challenge was to demonstrate how the interaction happened. He started by measuring local blood flows as a marker for energy changes. He studied patients who had undergone brain surgery and were left with holes in the cranium, over which the brain was covered only with dura mater and skin. By placing small plethysmographs onto these gaps he measured changes in pressure after mental stimuli (light, sounds, thoughts) as a gauge of local blood flow. He noted increases in flow with pleasant sensations and decreases with unpleasant ones. Although interesting, the work was fraught with technical difficulties. These studies, however, were the forerunners of the ubiquitous functional MRI scans of today that demonstrate changes in regional blood flow in response to mental phenomena.

     He then tried measuring brain temperatures during brain surgery and recorded changes on emerging from anesthesia, during arithmetic calculations, etc. Though he generated much data, nothing meaningful came of it. So he turned to looking at electrical energy. Berger applied pairs of tiny electrodes under the  scalp, first in patients with cranial defects (later flat electrodes over intact skull). He used a sensitive string galvanometer made for EKG, moving later to more sensitive Siemens oscilloscopes. 

From Berger's first publication. Top line is EEG from 2 leads on scalp of 36 year-old bald male, placed
 fore and aft. Second line is EKG, third line is clock at 1/10 second intervals.

     Various stimuli, such as opening the eyes to bright light, produced different patterns, as previously seen in animals. He viewed seizures as an example of the consumption of all available brain energy, thus explaining the sleep that followed a seizure. He identified the basic alpha and beta wave patterns, though his interpretations have been modified.

     During this work Berger became secretive, working alone, avoiding discussions of his ideas with colleagues and in his lectures. His diaries indicate a depressive state of mind, frequent discouragement and insecurity. Finally, in 1929, after about 5 years of work, he published what is now a “classic” paper: “On the Human Encephalogram” (Über das Elektrenkephalogramm des Menschen), coining the new term “encephalogram” in the paper. Other papers followed.

     The work was received with some apathy in Germany, but was picked up by others, especially by Edgar Douglas Adrian at

Edgar Douglas Adrian (Wikipedia)

Cambridge, who was recording electrical impulses from individual axons (and who won a Nobel Prize in 1932). Adrian expanded the EEG work, opening it to the wider scientific community, and making Berger well known outside Germany.

     Berger fell in love with a laboratory technician before WWI, a Baroness - Ursula von Bülow, whom he married despite the social difference between them. He was called away during WWI as a psychiatrist near the Western front, but had few duties. Over time he was promoted and became a  professor and director of the Neurology and Psychiatric Clinic at  Jena University. He is described as an excellent diagnostician, but made almost no close friends and was considered “shy, reticent, and inhibited” by a colleague (Ginzberg).

University of Jena about 1910 (Wikipedia)

     As Nazism penetrated Germany in the 1930s the University of Jena was affected. Berger did not like the Nazis, did not join the party, and any papers he gave abroad had to be censured. But it has been recently reported that Berger accepted a position on the Erbsgesundheitgericht, the Court for Eugenics, in Jena. Nazi Germany had passed several eugenics laws, allowing for the sterilization of persons with various categories of neurologic and psychiatric diseases, such as dementia, deafness, multiple sclerosis, alcoholism, etc. Methods included tubal ligations, vasectomies, and radiation of gonads. Berger served on two levels of the regional Court, passing judgment on cases for sterilization during 1938.    

     On reaching age 65 that year he took mandatory University retirement and left the Court. His previous congestive heart failure worsened and he became more depressed. A final diary entry speaks of despair, sleepless nights, brooding, self accusations, and includes,"...I yearningly wished for my early end"(Gloor). Ten days later he committed suicide by hanging.

SOURCES:

Gloor, P. "Hans Berger and the Discovery of the 

      Electroencephalogram". Electroencephalography and Clinical 

      Neurophysiology, 1969, Suppl 28, pp 1-36.

Ginzberg, R. “Three Years with Hans Berger: A Contribution to  

      His Biography. J Hist Med and Allied Sci. 1949, pp 361-71.

Millett, D. “Hans Berger: From Psychic Energy to the EEG”. 

       Perspectives in Biol and Med, 2001. 44(4): 522-42.

Berger, H. “Über das Elektroenkephalogramm des Menschen”. 

       1929; Arch Psych und Nervenkrankeiten, 87: 527-70.

Zeidman, LA, et al. “New Revelations About Hans Berger, Father  

       of the Electroencephalogram (EEG), and his Ties to the Third 

        Reich”. 2014; J Child Neurology 29(7): 1002-1010.

Finger, S. Minds Behind the Brain: A History of the Pioneers and   

        their Discoveries. 2000, Oxford U. Press.