Though the idea of removing “sympathetic” responses by leeching blood thankfully did not survive, Broussais’ intensive discussions, arguments, and occasional harassment of a junior colleague at the University of Paris proved to be one of his greatest contributions. Gabriel Andral was born a generation after Bichat and Broussais. Like these two older figures, Andral’s father had served as a military physician in the Revolutionary Army, being the personal physician to Marshall Joachim-Napoleon Murat (Bonaparte’s brother-in-law).41 Unlike these solider-physicians of an earlier generation, Andral was armed with a far more powerful weapon than anything wielded by Bichat or Broussais: a microscope. As we will see in the next chapter, the microscope had existed for many generations before but had rarely been deployed, due to the secrecy of its inventor. Once the technological challenges were solved and the instrument became widely used, the field of microscopy radically revolutionized our understanding of health and disease.
For many decades, it was known that blood contained troves of small red blood cells (erythrocytes). Unreported until Andral was evidence that much more was present in blood than could possibly have been anticipated. For example, Andral noted that a small minority of blood cells lacked the erythrocytes’ red hue, which is due to iron in the hemoglobin of red blood cells.42 Red blood cells shared an almost universal size, color, and shape (the rare exceptions being cells from patients with sickle cell anemia), but Andral noted the presence of leukocytes (a Greek term meaning ‘white cells’), which lacked a fixed shape or color. Unlike erythrocytes, they also had a prominent nucleus (a structure that we now know contains the cells’ DNA; erythrocytes uniquely lack a nucleus or genomic DNA). Furthermore, Andral noted a variety of different types of white blood cells, as well as the presence in the blood of what he referred to as “humors,” which regulated the composition and actions of the many different types of cells in the blood.43 This idea of bodily humors was ridiculed by many contemporaries, most notably Broussais. Ultimately, Andral prevailed, both because he replaced Broussais at the University of Paris and because his description of the different cells in the blood and the factors affecting them gave rise to a new medical field focused upon diseases of the blood: hematology.
Since the time of Andral, our understanding of hematology and the immune system has continued to grow exponentially. Typical academic texts on even the most basic aspects of the subject routinely exceed many hundreds of pages. Here we will convey an overly brief and admittedly superficial summary of a host defense mechanisms and how they function to keep the body safe from dangers, both internal and from a hostile world.
The human immune system comprises a series of layered defenses structured in a manner surprisingly like modern warfare. The front line in the war against invaders is an ancient physical barrier comprising human skin and the lining of our internal tissues. Although skin is the focus of billions of dollars in cosmetic, pharmaceutical, and surgical enhancement procedures, it is greatly underappreciated in terms of its importance as the first line of defense in preventing disease. At the risk of offending those enamored with the exquisite and undeniable beauty and complexity of the human body, consider that each of us is simply a tube within a tube. The outer tube is the body. This tube has a large surface area (e.g., skin) and occasional holes (e.g., eyes, nose, and genital orifices), which must be patrolled to halt myriad pathogens in an environment that even the most maniacal hygienist cannot (and should not) keep clean. A second, inner tube comprises the digestive tract, which is a large hole that penetrates all the way through the outer tube. Interspersed over this extensive framework, on both the inner and outer surfaces, are arrays of cells tasked with detecting and eliminating harmful microorganisms within a wet, warm environment ideally suited to most germs. Thus, the body has developed an array of mechanisms to help detect and eliminate harmful invaders.
Like the guard posts that line the defensive perimeter of a battlement, clusters of immune tissues are interspersed all along each tube in the body and its entry points. Prominent among these are structures known as lymph nodes, small kidney-shaped structures normally smaller than a half inch in diameter. As we have already seen, the detection of a foreign invader can trigger the production of cytokines, which mobilize the cells of the immune system to swarm into a nearby lymph node in an early attempt to limit the infection. As the defense mounts, these outposts enlarge. Examination (palpitation) of the lymph nodes has become a routine part of a clinical examination. Returning to our story, the breaching of these fortifications (i.e., lymph nodes) was responsible for the exudates of pus that Chauliac witnessed as they erupted from the bubos (lesions) of plague victims.
The lymph nodes are well-organized fortresses designed to sample the fluids of the body to detect, isolate, and destroy potential invaders. This process entails a complex association of many different white blood cells. The catch-all term of white cells distinguishes them from the red blood cells witnessed by Anton van Leeuwenhoek. While we focused on discovery of leukocytes by Andrai in France, the practice of discovery often arises in multiple places at once, and comparable contributions were made by Gottlieb Gluge in Belgium, William Vogel in Germany, and William Addison in Britain.44 Many of the leukocytes identified by these investigators include adaptations and improvements of ancient phagocytic cells as detailed above. Not only do these cells engulf and destroy pathogens such as bacteria but they also produce cytokines to alert the body that it is under attack and drive host defense cells to gather at these sites of infection. To understand how we gained understanding of the many cells that contribute to host defense, we now turn to one of the most important figures in the history of medicine, Paul Ehrlich.
Enter Ehrlich
In 1854, Paul Ehrlich was born in a small town in Lower Silesia (now Poland) to a family of distillers and tavern managers. During his adolescent education at the Maria-Magdalenen Gymnasium in nearby Breslau, Ehrlich began a lifelong friendship with Albert Ludwig Sigesmund Neisser. This connection is notable in part because Neisser would later discover the bacterial pathogen responsible for gonorrhea (and later still, the microorganism that causes leprosy), while Ehrlich’s later contributions to medicine included arsphenamine, the first successful treatment for gonorrhea. Ehrlich’s early education was also notable for the fact that he followed in the footsteps of his cousin, Carl Weigert, nine years his elder, who also attended Maria-Magdalenen Gymnasium and became fascinated with the emerging field of chemical dyes (in contrast to relatively rare and more expensive natural dyes such as indigo).
In the 19th and early 20th centuries, Germany reigned supreme in the science of creating and manufacturing dyes and other chemicals for use in the manufacturing of clothing, printed goods, and consumer products.45 Weigert’s seminal contributions to medicine included demonstrating that a set of dyes derived from coal tar could be used to stain certain human tissues (helping modernize the field of histology).46 Carl Weiger’s first report demonstrating the use of aniline to study human tissue was published in 1871, six years before Paul Ehrlich’s first scientific publication.47
The chemical dyes and bacteria that captured the imaginations of Weigert and Ehrlich were quite the rage among late-19th-century German scientists. Arguably, the fascination began with the discovery of a link between bacteria and disease as revealed by the Prussian scientist Theodor Albrecht Edwin Klebs, who used these dyes and a simple microscope to identify bacteria in the mucus of individuals suffering from pneumonia (and who is honored with the eponymous name of a major causative agent of pneumonia, Klebsiella pneumoniae). It seems that Klebs was a rather cantankerous character. His 1913 obituary in the prominent Science magazine attributes his impulsive and combative style to a genetic predisposition representing “the Slavic element in his composition.”48 Klebs’s combative style likely also reflected the environment in which he trained. His principal mentor, Rudolf Ludwig Carl Virchow, was referred to as the “Pope of Medicine” and is remembered today not only for his many contributions
to science but also for his public denigration of colleagues with whom he disagreed: he pinned the title of “ignoramus” upon Charles Darwin and publically branded his student, the prominent naturalist Ernst Haeckel, as a “fool.”49 Virchow’s passion for socialist causes led him to politics, where he served more than a dozen years in the Reichstag and cofounded the Prussian liberal party. These experiences also revealed an audacious character, as evidenced by his well-publicized criticism of the Bismarck government, which led to his being challenged to a duel by the great statesman. In an apocryphal story, Virchow reportedly responded by agreeing to the duel only if he could choose the weapon: a Trichinella-loaded sausage.50 As we will later see, this is not the only time that German wurst enters our story.
Returning to Klebs, the link between bacteria and pneumonia was intriguing but indirect. A contemporary of Virchow, the Silesian physician Carl Friedlander, built upon Klebs’ work and revealed in 1882 that the cause-and-effect relationship between the bacterium and pneumonia was absolute.51 This pronouncement was antithetical to many in the Prussian scientific establishment, who maintained a myth propagated since the times of ancient Greece that bad air (or miasma) was the cause of such diseases. Despite the growing criticism, Friedlander recruited a junior Danish scientist by the name of Hans Christian Gram to join his pathology laboratory in October 1883. Within two weeks, Gram identified a chemical dye, known as aniline gentian violet, that would selectively stain bacteria. By combining this “Gram stain” with a dye pioneered by Ehrlich, Gram would help dispel such outdated notions.
After graduating from the gymnasium, Ehrlich trained in medicine at multiple institutions throughout Germany, receiving his doctorate at nineteen years of age. Five years later, Ehrlich utilized aniline and other chemical dyes to stain the cellular components of blood. These studies revealed distinct populations of leukocytes, based on their ability to uptake or exclude various dyes. For example, one type of phagocyte was and still is referred to as an eosinophil for its ability to be selectively stained with the dye eosin.52 Another population of cells, known as basophils, were so-named for their ability to take up basic dyes (-phil is an ancient Greek suffix meaning ‘love’ or ‘affection,’ as used in words such as Anglophile). Three years after publishing his study of blood cells, the junior Ehrlich attended an 1882 seminar given by the illustrious Robert Koch, which would change the lives of both researchers as well as the worlds of science and medicine forever.
Koch himself was a precocious child, who shocked his parents at the ripe age of five with the revelation he had taught himself to read.53 After training in medicine, Koch became interested in understanding the causes of infectious diseases (which was still governed by superstitions such as “miasma,” or bad air, as the basis of many diseases). Utilizing the still-emerging field of microscopy, Koch founded a new field: bacteriology. In 1876, Koch isolated a putrid organ from an anthrax-infected animal and isolated a bacterium, now known as Bacillus anthracis, thereby demonstrating the cause of anthrax.54 Koch cultured the bacterium in the laboratory by isolating the exudate from infection onto a slice of potato to provide a source of nutrients for the microorganisms living within. After waiting a few days, Koch spied little white bumps on the potato, which contained millions of individual bacteria. He found the growth was optimal at body temperature (98.6˚F or 37˚C). Unfortunately, not all bacteria were amenable to being grown on a potato slice, and the vegetable medium was itself not ideal, as it tended to soften and disintegrate, particularly under the relatively warm conditions favored by bacteria.55
Fortunately for Koch, his studies to purify and then identify the biological agent that caused anthrax and other bacterial diseases were aided by a rather extraordinary team. One team member was Walther Hesse, a pathologist, who came from a large family of physicians (four of five brothers became doctors or dentists) in the east German region of Saxony. After obtaining medical training in Leipzig, Hesse served as a rural physician before volunteering for the Prussian army in 1867. This adventure led to his participation in the battles of Gravellote and St. Privat during the Franco-Prussian War of 1870–71. Hesse’s frustration about the sanitation and logistics of the army hospitals revealed his early leanings towards academia.56 Hesse briefly returned to eastern Germany after his discharge from the army in 1872. He tried to settle down as a physician in Dresden, but wanderlust led him to serve as a ship’s surgeon on a German passenger ship (the New York Line). This decision also afforded Walther an opportunity to visit one of his brothers, Richard, who had established a successful dental practice in Brooklyn. During this time, Hesse became interested in the subject of seasickness (which engrossed him during his two-year stint on the passenger liner) and penned what has been described as the first objective scientific treatise on the subject. While Walther was on a North American layover in November 1872, Richard introduced him to New York society—specifically to the Eilshemius family, a family of successful Dutch importers. The eldest daughter, Angelina (Fanny), apparently caught Walther’s eye. Their first meeting was cut short by Walther’s need to return to his work, but Fanny was planning her Grand Tour of Europe (as was the custom with many wealthy Americans). While the trip was intended to focus on Switzerland, Fanny convinced her younger sister to join her on a diversion to Dresden in Saxony. Walther’s return to Dresden (or more specifically the suburb of Zittau) might have been based in part on the fact that the medical community had learned of Walther’s work on motion sickness and awarded him membership in their medical society. Impressed by the shimmering Saxon capital (described at the time as the Florence of the Elbe River), Fanny fell in love with Dresden and with Walther, and the two were married in Geneva the following summer (during the family’s next excursion to Switzerland). Walther was later promoted to become the lead county physician in charge of Schwarzenberg im Erzegebirg, a mountain region near the Czech border. Mining for heavy metals such as uranium was the primary industry of the region. It was accompanied by myriad diseases, infectious and otherwise, associated with the poor working conditions and environmental damage of the heavily mined region. Such widespread malaise was not questioned and simply accepted by most doctors, both in Schwarzenberg and elsewhere in the world, at least until the arrival of Walther Hesse in Schwarzenberg.
Upon his arrival, Walther considered that the poor environmental conditions might cause an increase in airborne infectious agents and thereby contribute to the high disease burden in Schwarzenberg. This question drove Hesse to become interested in bacteriology and ultimately led him to take an academic sabbatical with Robert Koch. All the while, the well-educated and equally curious Fanny worked with Walther, often behind the scenes. Like her younger brother Louis Michel Eilshemius (who is now considered a leading figure of naïve art), Fanny had a talent for art. She became heavily involved in documenting Walther’s work pictorially and joined him for his sabbatical.
During the Hesses’ sabbatical, Koch was trying to identify ways to replace potatoes while culturing bacteria. One of his assistants, Julius Richard Petri, had created a small dish that still bears his name to this day, but what to put in it? An early experiment tried to utilize gelatin, but this material tended to liquefy in the warm and humid lab environments preferred by bacteria. These setbacks proved worrisome for Walther’s attempts to identify bacteria in the air.
In addition to her artistic abilities, Fanny was an expert in making jellies and American-style puddings. Walther and Fanny realized that the solid consistency of these jellies, even on the warmest summer days, might provide an answer. Drawing from her upbringing in New York, Fanny had prepared her famous jellies using agar rather than gelatin. This East Asian culinary trick was learned from Fanny’s childhood neighbor, a Dutch woman who had immigrated to New York from Java (at the time, a Dutch possession). Returning to work with a solution to the long-standing problem, Walther was feted by Koch, as this breakthrough greatly accelerated ongoing studies of tuberculosis and other infectious diseases (though neither Walther
nor Fanny were credited for their contributions). Unperturbed by this oversight, Walther and Fanny returned to Dresden, where Walther continued his research in public health, with emphasis upon plague research. Upon his death in 1911, his laboratory had to be burned to the ground, since the magnitude of contamination was such that it was considered a public health threat.
While Petri and the Hesses were optimizing the technical necessities needed to culture bacteria, Koch was outlining the criteria that must be met to irrefutably link the cause of a disease with an identifiable bacterial pathogen. As spelled out by Koch in 1880, the criteria required that the responsible pathogen be present in every case of the disease; it could be isolated and cause disease in a healthy subject; it could again be isolated from the subject who had been infected. These simple rules created a much-needed standard for linking a microbial agent with disease. The prescience of Koch’s postulates continues even today to overturn inaccurate conjecture about disease causes (including objective resolution of controversies linking HIV with AIDS, or Zika virus with microcephaly). Known as Koch’s postulates, these assertions provided the cornerstone for understanding communicative diseases and utterly dispelled age-old superstitions, including miasma.
Given the impact and fame that accompanied Koch’s discoveries, he was invited to give talks all throughout Europe. An 1882 seminar on the cause of tuberculosis was attended by a twenty-something Paul Ehrlich. Ehrlich was so impressed with Koch’s demonstration of an assay to detect what is now known as Mycobacterium tuberculosis that he went straight back to his laboratory to test the idea. Within a day, Ehrlich had dramatically improved the assay and reported these results back to Koch. This interaction between a budding young scientist and his more senior (by more than a decade) counterpart began a professional and personal relationship that persisted throughout their lifetimes. Koch helped foster Ehrlich’s career and offered him a position in his laboratory, a considerable improvement as Ehrlich up to this time had performed his studies in his sparsely-appointed private laboratory (akin to the foundations of the computer age arising from work in a handful of garages on the American West Coast a century later). The partnership to improve the tuberculosis assay became quite personal for Ehrlich, as he used the technique in 1885 to self-diagnose his own disease after suffering from a persistent cough. As was common among those who could afford it, Ehrlich recuperated in the warmer climes of Egypt. Following his recuperation, Koch asked his friend to join him in Berlin in 1891 as a founding faculty member of the newly created Institute of Infectious Diseases, now known as the Robert Koch Institute.
Between Hope and Fear Page 11
