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Profiles in Leadership / The Geography of Immunology

Karl F. Meyer: The Renaissance Immunologist

by Charles Richter and John S. Emrich
June/July 2018, pages 22–27

In a career spanning 65 years and three continents, Karl F. Meyer (AAI 1922, president 1940–41), known as “K.F.” to his colleagues, was a true renaissance immunologist. He not only made numerous advances in the understanding of human and animal diseases, but also introduced revolutionary theories of disease transmission and successfully straddled the academy-industry line. He established the Department of Bacteriology at the University of California, San Francisco (UCSF), where he worked for over 60 years. His legacy of research, teaching, and service seems almost too great for one scientist

EDUCATION

Meyer was born in Basel, Switzerland, in 1884. His interest in pathology began in childhood, when his biology teacher brought fish with tumors or other anomalies to class for the students to examine. Young Karl was captivated by the possibility of looking at the specimen under a microscope and seeing a parasite that may have been the cause of the malformation. The role of parasites in disease was just beginning to be understood—Charles Louis Alphonse Laveran had first observed the malaria parasite with a microscope in 1880— so Meyer was experiencing a scientific revolution right in his classroom.

At the age of 18, Meyer enrolled at the University of Basel and, after one semester, transferred to the University of Zurich because of its renowned comparative anatomy department. He excelled in his studies there, passing first qualifying examinations in zoology, botany, physics, and chemistry with flying colors.

Because of his interest in tissue sectioning and microscopic structure, one of Meyer’s professors recommended that he study under Heinrich Zangger, a professor of physiology at the university’s veterinary school.

Meyer considered his move to the veterinary school to be the true beginning of his career. There, he was able to immerse himself in human and animal physiology and biochemistry. His second qualifying examinations were in anatomy, physiology, biochemistry, and histology, and led to his graduate study.

Arriving at the University of Bern for his doctoral thesis work in 1906, Meyer wanted to work in the laboratory of Theodor Langhans but was initially rebuffed by the eminent German pathologist. Two days later, while Langhans was performing an autopsy, Meyer decided to surreptitiously remove a sample of a jaw tumor from the cadaver, pickle it, and create sections in which he found liver cells. He took the slides to Langhans, who—without knowing where they came from—agreed with Meyer’s diagnosis of a teratoma. When Meyer told him where he had acquired the sample, Langhans was so impressed by the speed and quality of the sections that he hired him on the spot for his lab.

Because of the oddities in the Swiss university system and Meyer’s diverse work with many advisors, his D.V.M. was awarded by the University of Zurich in 1909 even though he did none of his actual graduate work there.

EARLY CAREER

Soon after receiving his doctorate, Meyer went to work in South Africa with the Swiss veterinarian Arnold Theiler. He intended to assist in the manufacture of rabies vaccine for local use at the Onderstepoort Veterinary Research Institute. His duties quickly multiplied there and he eventually butted heads with Theiler, founder of Onderstepoort and pillar of veterinary sciences in the country. They disagreed whether African East Coast Fever (theileriosis) could be transmitted in the absence of ticks. When Meyer successfully demonstrated both transmission and possible immunization of the disease through tissue transplants, contrary to Theiler’s previously published research, Theiler demanded that the results be published under his name as the director of the institute. Meyer refused, and the two never spoke directly to one another again. Eventually, Theiler had to admit that he had been wrong, but Meyer was long gone from Africa by that time.

In 1910, Meyer came to the United States when he accepted the position of assistant professor of pathology at the University of Pennsylvania. Although the intellectual community of Philadelphia welcomed him, he later recalled finding his students at Penn disappointing, and constantly feeling like an outsider at the university. But his experiences in South Africa garnered him invitations to join the Pennsylvania Livestock Sanitary Board and the Philadelphia Milk Commission; both provided satisfying and familiar challenges. His experiences with these industry-related organizations would prepare him for a long legacy of consultation to ensure food safety.

In these first few years in the United States, Meyer also had opportunities to meet many of the giants of early immunology at Penn and at scientific meetings, including John A. Kolmer (AAI 1913, president 1917–18), Victor C. Vaughan (AAI 1915), and Theobald Smith (AAI 1920). They helped convince him that the United States was “worth staying around for.”

Then in early 1913 a new opportunity arose. Meyer went for lunch with his colleague at Penn, Richard M. Pierce, who immediately told him, “You’re going to California.” Not only did Pierce have a lead on a job working with Frederick P. Gay (AAI 1918, president 1921–22) at the University of California, Berkeley, but he had also heard about the enormous grant from the Hooper family to establish an institute of medical research at UCSF, which Pierce believed could become “the Rockefeller Institute of the West.”

Meyer was initially skeptical about moving to California, but he took the job at Berkeley and, in 1915, also joined the faculty at the newly established Hooper Foundation at UCSF. This was the first medical research foundation in the United States to be incorporated as a university department and he became its second director in 1921. After crossing the equator twice, the Atlantic Ocean and the United States once, and countless time zones, Meyer finally found a permanent home in the Golden State, where he remained affiliated with both Berkeley and UCSF in various capacities for the rest of his life.

In California, Meyer found the freedom he had long sought to explore his many immunological interests. He could investigate a particular topic, move on to another problem, and return to the original matter with new insights. Over his long career one constant was his drive to understand how diseases could lie dormant and unnoticed for years before producing a sudden outbreak. His work on disease cycles led him to introduce a new concept: reservoirs of disease. This line of thinking was instrumental in fighting plague in the American West and also helped him develop effective methods to ensure food safety across multiple industries.

LATENT INFECTIONS AND RESERVOIRS OF DISEASE

The myriad of diseases that Meyer had studied led him to reconsider the basic relationship between humans, animals, and pathogens. He argued that it was wrong to approach infections “from the standpoint, not of the agent, but of the altered state of the host—the disease.” The ability to identify subclinical infections had proven this approach untenable. Instead, by the 1930s, Meyer wanted to base disease research on the “biologic definition of an infection as a host-parasite relationship.” A notorious tainted spaghetti casserole incident two decades earlier helped lead Meyer toward this way of thinking about disease.

In the days following a 1914 church dinner in Hanford, California, 93 people who had eaten food from the dinner contracted typhoid fever. Meyer was part of the team led by Wilbur A. Sawyer, director of the Hygienic Laboratory of the California State Board of Health, that investigated the cause of the outbreak. By interviewing the typhoid patients in the growing San Joaquin Valley town about the dishes they had sampled and cross-checking against the menu, it was determined that the culprit was a baked spaghetti dish.

Among those who participated in preparing the dish was a boarding-house operator whose medical history suggested she was likely a typhoid carrier. By preparing replica casseroles inoculated with typhoid, Sawyer showed that it would have been impossible for the spaghetti to have been heated sufficiently to kill the typhoid bacteria. When Meyer dug into the story, he felt it was emblematic of “a lack of social consciousness” that pushed him to advocate for public health and preventive medicine. To do this, he would have to understand why some infections remained latent but transmissible.

A recollection from his early days in Zurich at the turn of the century provided some insight: in the autopsy room, 98 percent of people who died from causes other than tuberculosis nevertheless had tubercle lesions, leading Meyer to call the population “tuberculinized.” In the early 1920s, Meyer and his colleagues started to think about infection from the perspective of a parasitologist, noticing that “when you had a roundworm or flatworm infection, you frequently didn’t show any symptoms at all.” By 1928, he was in the practice of referring to bacteria and viruses as “parasites” and considering “the ability of the animal or the man to accept this parasite” as a critical element in the transition from infection to disease.

Around 1930, an abnormally high incidence of tularemia infection among people bitten by dogs in Sonoma County caught his attention, and he soon had a eureka moment. Although the dogs showed no clinical signs of the disease, upon examination, they were found to have produced antibodies against the bacterium. The dogs were latent carriers, transmitting tularemia from a larger reservoir of infected rabbits to unfortunate humans.

In his 1931 Ludvig Hektoen Lecture, Meyer articulated the theory of the animal kingdom as a reservoir of disease and hoped that this model would lead to novel approaches for dealing with emerging zoonoses. Eventually, he catalogued dozens of diseases by their specific animal carrier paths, allowing him to recommend likely strategies for diagnosis and elimination, including destruction of infected animals, vaccination where possible, or abatement of insect vectors.

PUBLIC HEALTH AND SAVING INDUSTRIES

Throughout his career, Meyer worked with various food industries to improve food safety, sometimes saving them from complete ruin. Very soon after arriving in San Francisco, he questioned the testing methods for bovine tuberculosis and arranged with the San Francisco Milk Commission to test the milk supply. He discovered that none of the certified milk carried tuberculosis, but “all the first-class milk in San Francisco was infected with Brucella.”

This finding led to extensive study on the pathogenicity of Brucella, especially in infants. In the course of the milk investigations, one dairy was found to be producing milk contaminated with human streptococci, which was causing septic sore-throat epidemics. Meyer’s team cultured every worker in the dairy, and if they found one infected with hemolytic streptococci, the worker had a choice: “he was either discharged, or at the expense of the Milk Commission, he was tonsillectomized.”

In 1919, Meyer was brought in to advise an informal consortium of California’s largest canning companies on the problem of botulism in canned food, as he had taught courses on anaerobic infections during the First World War. Tainted California olives had caused deaths in the Midwest, leading to quarantines on all California canned goods in Michigan and Ohio. Some canners were ready to stop canning olives altogether. Meyer, recognizing that the canners did not have a scientifically sound method for food sterilization, exploded at this proposed solution:

Absolutely no! Because your whole canning procedure is empiricism. I can just visualize what happens. You figure on the cuff of your shirt the time and temperature which you think is necessary to sterilize the product. Then you put it in a retort which is not controlled. After having given it a cook for such-and-such a time it goes in the warehouse, and if it doesn’t blow up in the next forty-eight hours, this thing is safe.

Convinced that Meyer could provide an effective research plan to eliminate botulism, the director of the National Canners Association asked him to present the canners with a budget the next morning. Meyer and Ernest Dickson of Stanford sat down at the Pig’n Whistle restaurant in downtown San Francisco and worked out an annual budget over tea. When Meyer tabulated it at $30,000, Dickson slumped in his seat, thinking the canners would never underwrite such an amount. Nevertheless, Meyer took the budget to the meeting with the canners.

R. I. Bentley, president of the California Packing Corporation, pointed out that his company alone was losing $70,000 a week under the Midwest quarantines, so the research proposal was easily justified. Even in 1919, canning was a multi-billion dollar industry.

Over the next three years, Meyer developed techniques for testing and sterilizing canned foods that would reliably neutralize any Clostridium botulinum spores without destroying the food itself. Later in life, he joked that he had become “one of the most fantastic parasites” on the big canning companies—a parasite that they could not live without.

PLAGUE

Plague, in all its manifestations, had fascinated Meyer ever since his time in Africa, where he saw cases of the disease firsthand. When he arrived in San Francisco, the city had recently experienced a number of outbreaks spread by rats around the port. These included a nearly four-year (1900– 1904) bubonic plague epidemic centered in the Chinatown section, and another following the 1906 earthquake.

In the rural areas far from the port, however, reports of plague posed a medical mystery in that they contradicted the current medical theories on the transmission of the disease. According to the leading theory about plague, a rat was a necessary vector to transport the fleas that carried the disease.

In 1903, federal investigators found that workers on the Southern Pacific Railroad had contracted bubonic plague despite no evidence of contact with rats. Four years later, a fatal case of plague in Contra Costa County provided new clues as the investigation focused on local ground squirrels, which were found to be widely infected. Almost immediately upon arriving in California in 1913, Meyer had his first opportunity to see for himself how the U.S. Public Health Service (PHS) handled plague research under George McCoy (AAI 1916, president 1922–23). Meyer learned how to identify plague via dissection of ground squirrels and was struck by how many infected animals the federal researchers discovered, confirming once and for all, that wild rodents were carriers of plague. But two years later, the PHS did something that Meyer considered “most unfortunate”—it announced that the fumigation of ground squirrel burrows had eradicated plague from California. Of course, these measures had not actually solved the problem, and Meyer was asked to consult on a pneumonic plague outbreak in 1919.

Meyer was never one to allow himself to be confined to the lab; he was just as likely to be in the field hunting squirrels for dissection. A major breakthrough came in 1924, when squirrel fleas were found on rats in the middle of an outbreak in Los Angeles. Meyer began to believe that “under certain conditions squirrel plague could have been transmitted to rats and in rats it began to burn in a typical rat epizootic.” After a similar outbreak in 1928, Meyer coined the term “sylvatic plague.” Unlike bubonic or pneumonic plague, sylvatic plague refers not to the type of Yersinia pestis infection, but rather to the reservoir of the bacterium situated in the wild rodent populations. Under Meyer’s theory, plague outbreaks were not dependent on foreign vectors entering a port—the disease had made itself at home in the United States.

Human cases of plague kept appearing in places where no evidence of the disease had been found in the local fauna; to Meyer, this simply meant that existing methods of detection were inadequate. Taking a cue from the old practices of the famed Japanese bacteriologist Kitasato Shibasaburo, who is credited with co-discovering the infectious agent of bubonic plague with Alexandre Yersin in 1894, Meyer began combing fleas from wild rodents and inoculating the fleas. This technique revealed that although there were no gross lesions in any of the thousand rodent specimens, samples from five percent of the fleas produced fatal plague in guinea pigs. From this data, Meyer hypothesized that the persistence of plague in a given area was dependent on how resistant the local rodent populations were. This new way of thinking about disease would soon dramatically alter public health strategies in California and the wider American West.

By 1935, the PHS and the California Department of Public Health were working with the Hooper Foundation to find and study plague throughout the Western states. They soon identified reservoirs in at least 12 states, in populations of ground squirrels, wood rats, chipmunks, prairie dogs, and marmots. Eventually, hundreds of wild rodent species were discovered to be carriers of plague. These discoveries led to the first wide-ranging rodent abatement programs on military bases, beginning close to San Francisco at Fort Ord.

To study the transmission of Yersinia pestis more closely, Meyer sought to construct an entire “town” for his ever-increasing plague research. UCSF told him that it was too dangerous to “work with the black death” on campus, but the Rosenberg Foundation donated funds for a special secure laboratory where the work could be done safely. One room held what became known as “Mouse Town, U.S.A.”—a large mouse enclosure split down the middle to allow tests of transmission and prophylaxis. The floor of the room was sprinkled with crystals of DDT and kept spotlessly white so any flea that managed to hop the walls of Mouse Town would be immediately visible.

Meyer placed 100 mice on each side of “town” and dosed the water of the west side with sulfadiazine. He then allowed 800 plague-infected fleas to invade Mouse Town with the freedom to cross the central barrier. Within days, plague was raging on the east side, but the sulfa-dosed mice on the west side remained healthy. Meyer’s findings in this and other Mouse Town experiments led to antibiotic prophylaxis methods to prevent plague infection, as well as improved vaccines for plague. The isolation unit produced millions of doses of effective plague vaccine for military use: in 1964, not a single case of plague was reported throughout the U.S. armed forces, even among troops stationed in areas where plague infection occurred in the local population.

Karl F. Meyer’s tireless research was so foundational and wide-ranging that he won the 1951 Albert Lasker Basic Medical Research Award. This honor was not for any single discovery, but for “Mechanism of parasites infection”—a fitting summary of decades of work. The Lasker committee recognized that Meyer bore:

... a major share of responsibility for the control of botulism, and for a classification and international identification center for the clostridia; for our recognition that plague is sylvatic, not merely rat-borne; for understanding of the broad spectrum of brucellosis rather than restricted goat-borne Malta-fever; for the concept of ornithosis rather than psittacosis; for elucidating the role of the arthropod vector in western equine encephalomyelitis; for showing that western ticks are also responsible for relapsing fever; for studying the dinoflagellate causing mussel poisoning; for increasing our knowledge of leptospirosis; for valuable assistance with investigations of Q fever.

In addition to his research, Meyer offered his professional service to government advisory committees, the National Academy of Science, the World Health Organization, and many professional organizations, including AAI. He served as the 27th president of AAI and, for over two decades, as an editor for The Journal of Immunology. He was also a dedicated, creative, and memorable educator who left his mark on generations of doctoral students. Meyer was a true renaissance immunologist whose wide-ranging work was invaluable to the field.

 

References

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