by Bill Hayes
In Marquardt’s affectionate work as well as in the drier tomes of Ehrlich’s fellow scientists, a telling quirk surfaces: The man loved colors. He was “emotionally swayed” by them, one gentleman wrote. What spring is to a parfumeur, colors were to Paul Ehrlich. Though always a busy, busy man, Marquardt revealed, the doctor would still stop to extol the roar of yellows and reds in a bouquet of flowers. They “would make him quite ecstatic,” Marquardt admitted. This quirk carried over into his work habits as well. He wrote daily notes to himself and his staff on precut squares of different-colored construction paper, using various colored pencils. He kept this stationery in his coat pocket and, while he rarely lost his temper, he’d become terribly agitated if his supply ran out. (A similar response arose regarding his stock of Havana cigars, one of which was ever present, a sixth digit on his right hand.) Though surrounded by colors, none were more eye-popping to Dr. Ehrlich than those produced by his chemicals—the pure blues of cobalt compounds, glowing like the core of a torch flame, the delicate sea greens of iron-infused solutions. Far more than a source of pleasure, though, color was the prism through which he viewed and attempted to unravel biological mysteries. Color is the thread that links his disparate scientific achievements.
Born in 1854 in a small village 150 miles southeast of Berlin (an area that’s now part of Poland), Paul Ehrlich was the only son of prosperous Jewish parents who operated an inn. During his midteens, he pursued his keen interest in science under the watchful eye of a cousin on his mother’s side, Carl Weigert, who was nine years older than Paul. Weigert, a famous pathologist, had discovered that aniline dyes—synthetic dyes developed in Germany around 1860 for use in the textile industry—were unexpectedly well suited for staining human and animal tissue. Rather than obscuring details, these intense dyes instead illuminated them, revealing contrast and texture, making microscopic specimens easier to analyze. Weigert introduced his cousin to this important advance, and Paul began experimenting on his own. In 1872 he went off to study medicine at the University of Breslau and, as was customary in those days, transferred to different schools every year to train with the finest teachers. At the University of Strasbourg, while under the tutelage of one of the great anatomists of the nineteenth century, Wilhelm Waldeyer, Paul invented a technique that took his cousin’s discovery one step farther: “selective staining.” Using a dye of his own formulation, he found that each cellular element in a tissue sample reacted differently to his staining and also displayed a different shade, thus permitting extraordinarily sharp definition—akin to what HDTV is to regular television, I imagine. With this method, Paul promptly made his first major discovery: the mast cell, a type of cell common in connective tissue.
Praise for his innovative staining was not unanimous, however. While completing his studies at the University of Leipzig, Paul lived at a boardinghouse whose owner would recall many years later that the young student often looked like a human drop cloth; his hands, face, and clothes were always spotted with inky stains. His bath towels and linens were equally blemished, and no amount of washing could remove the blight. Moreover, even the house’s billiard table, upon which, for lack of flat surfaces, Paul had conducted experiments, was forever splotched with fuchsia, indigo, and lilac. Little could the proprietor have known then that her boarder’s messes would lead to findings that would make a permanent impact on several branches of science. Ehrlich had not been content simply to observe the myriad cells of the human body—as dazzling as he found them—but sought to figure out why dyes became fixed in specimens (as they did in fabrics), plus why individual cellular parts reacted so differently to certain dyes. From controlled experiments, he concluded that, rather than a mere physical change, a specific chemical transformation was occurring within the cells. These investigations into the nature of staining were the subject of Ehrlich’s 1878 doctoral thesis and also anticipated the dawning of a new field of biology, cytochemistry, the study of cell constituents. The thesis also contained the germ of a larger theory explaining how—in lay terms—disparate substances bind chemically, which would evolve over the next thirty years into his ideas about the formation of antibodies in human blood; his concept of a magic bullet; and, ultimately, the invention of the syphilis cure. But that’s jumping ahead.
Already renowned for his histological staining, the newly minted doctor was invited in 1878 to join the staff of the prestigious Charité Hospital in Berlin, where he worked under the supervision of Friedrich von Frerichs, an esteemed clinician. Though Ehrlich had a full roster of patients, Dr. Frerichs recognized the young man’s talent and energy and encouraged him to spend more time on original research. Ehrlich continued experimenting with aniline dyes but turned his attention from animal tissue to human blood, which, in a clinical setting, was readily available. The study of blood, too, was still fresh terrain. Although two centuries had passed since Antoni van Leeuwenhoek’s discovery of red blood cells, progress in the field of hematology had been sluggish. From today’s vantage point, it appears that Ehrlich was the right scientist at the right time and place, equipped with the right tools, to transform the entire discipline. Ensconced in his closet-sized hospital lab, the twenty-four-year-old quickly invented a simple method for preparing blood specimens. Well, simple for him. First he would take great care to spread a small drop of blood on a glass slide in the thinnest possible layer. He then allowed it to air-dry. Next, as he reported in a published paper, he heated the blood smear on a copper hot plate “for one or several hours” at 120 to 130 degrees Celsius, thereby fixing it and preserving the delicate cellular elements. Finally, he added one of his staining solutions. “Using such techniques,” Ehrlich concluded, “one can obtain with most dyes very beautiful and elegant pictures.”
Of great immediate significance were his “pictures” of white blood cells. Though a predecessor, the British microscopist William Hewson (1739–1774), had discovered white blood cells a hundred years earlier, he had supplied only sketchy details. (Medical historians now explain that white cells had been overlooked for so long not only because they’re far outnumbered by red cells, which make up 45 percent of blood volume, with white just 1 percent, but also—for me, the more convincing reason—because they are almost transparent.) Hewson also correctly surmised that white cells serve an infection-fighting role, in concert with the lymphatic system. Confirming Hewson’s theory, another British William, physician William Addison, demonstrated in 1843 that blood collected from an injured person’s wound had far more white cells than blood taken from elsewhere in that person’s body. Clearly, white cells were converging, but for exactly what purpose? Subsequent scientists, leading up to Ehrlich’s generation, discerned that white cells were, indeed, the army of the blood—helping defend the body against bacteria, fungi, and viruses. But it was Paul Ehrlich who first identified its main soldiers. By using his technique of selective staining, he differentiated the two broad classes of white cells, leukocytes and lymphocytes, and discovered three of the five specific types of white cells now known. He found he could illuminate each of these three using a different kind of dye. The names Ehrlich gave the cells were mini tributes to the dyes themselves: the eosinophil, which stained red from the eosin dye; the basophil, blue from a base dye; and the neutrophil, a pinkish color from a neutral dye.
Ehrlich’s heat-fixed blood-staining technique soon became standard practice, helping to usher the science of hematology into the modern age. Adopting his methodology, other scientists joined Ehrlich in making finer and finer distinctions about the behavior and function of both red and white blood cells, particularly in diseases such as anemia (characterized by a lack of hemoglobin) and leukemia (an overabundance of white cells). Likewise, quantitative blood counts were now possible and allowed for quick, accurate diagnoses of life-threatening conditions. The modern-day routine blood test called a CBC (complete blood count) is a direct descendant of Ehrlich’s innovation.
For his accomplishments, Ehrlich is now often lauded as the “father
of hematology,” a fact that calls for a small digression. Medical historians, I’ve noticed, demonstrate an almost comical penchant for assigning paternity to branches of science even if the field is already well populated with fathers. In my studies, Ehrlich is the fifth father of hematology I’ve come across, but this in no way minimizes his contribution. Among these patriarchs, though, Ehrlich stood out in one respect: He didn’t dote. While it is not unusual for a scientist to devote his or her life’s work to one specialty, Ehrlich tended to make discoveries and then, as I see it, abruptly move on. But he described it with greater eloquence: “One must not stay in a field of work until the crops are completely brought in, but leave still some part of the harvest for the others.” He moved on, again and again, to great success. Historians, in fact, also remember him as the father of histology, immunology, experimental oncology, and the aforementioned chemotherapy and cytochemistry.
Not all of Paul Ehrlich’s pursuits were academic, however. Five years into his tenure at the Charité Hospital, the then twenty-nine-year-old confronted a malady for which a cure is not always welcomed: lovesickness. The object of his infatuation was Hedwig Pinkus, a petite beauty ten years younger than him, the daughter of a prominent family from his hometown of Silesia. Though he squeezed in trips to visit her, Paul, for the most part, courted Hedwig through daily letters. An excerpt from one reveals a charmingly besotted man of science: “Although I am not allowed, dear Hedwig, to delight in your presence,” he wrote on March 2, 1883, “the thought of you has not left me for one moment. I must confess I am of no use at all for anything else, but I cannot help it. I have never been as unscientific as now. . . . My microscope is rusting, my beloved dyes are becoming moldy, the laboratory is collecting dust, and the [lab] animal keeper is shaking his head in disbelief.” Married in August 1883, the Ehrlichs settled down in Berlin; within a year the two became three with the birth of their daughter Stefanie.
A year before the birth of a second daughter, Marianne, Ehrlich’s life was shattered in March 1885 with the suicide of his revered mentor and ally, Dr. Frerichs. The pain of this loss was compounded by the frosty relationship he developed with his new boss, Frerichs’s successor, Dr. Carl Gerhardt. A stern taskmaster, Gerhardt decreed that Ehrlich must now devote the entirety of his time to patients. This abruption of his research could not have come at a worse moment. Ehrlich, using a dye called methylene blue in experiments with frogs, had just succeeded in staining living nerve tissue. This was a major technical breakthrough, for he, like other scientists, had always worked with inert samples of tissue and blood. Vital staining, as this was called, allowed him to begin examining the effect of chemical compounds on live cells, the important next step toward the crowning achievements of his career (a subject continued in the following chapter). But for now, this work would have to be shelved. Unable to pursue what he most loved, Ehrlich, miserable under Gerhardt’s command, finally resigned his post at the Charité after two years.
A tender moment between Paul Ehrlich (portrayed by an almost unrecognizable Edward G. Robinson) and his wife, Hedwig (Ruth Gordon), in a scene from the 1940 Warner Bros. film Dr. Ehrlich’s Magic Bullet
Complicating his decision—or perhaps, in a certain way, simplifying it—he’d developed a persistent cough from which he’d been unable to recover. Shortly after his resignation, he discovered evidence of tuberculosis in his own sputum (likely contracted from patients’ TB cultures), a finding that was sadly ironic because, just a few years earlier, he had invented the heat-dried staining method employed to make such a diagnosis. With a firm nudge from his worried wife, Ehrlich decided then not only to put his career on hold but also to take the radical step of leaving Germany altogether. At age thirty-four, he formalized plans to move his young family to Egypt, where he hoped he’d recuperate more quickly in the warm, dry climate.
Many years later Paul Ehrlich looked back on these final weeks in Berlin. During his lowest moments while working under Dr. Gerhardt, he recalled, those times when he felt bitter, dejected, he’d sneak away to his dusty laboratory, open the dye cupboard, and drink in the bright colors. He’d remind himself, “These here are my friends, who will never desert me.”
SEVEN
Detectable
BLOOD NEVER SLEEPS. EVEN WHEN WE’RE DEAD TO THE world, sad and torpid lumps under the covers of a sickbed, our blood is mounting its most vigorous defense. Here’s the drill: Approximately thirty minutes after we launch into sleep, the killers come out in full force—the “killer” T cells. Killer cells are lymphocytes, one of the five broader varieties of white blood cells. Their territory is our bloodstream and the connecting lymphatic tissue. Killers are created for a single purpose: to destroy foreign agents—viruses, bacteria, toxins. When a killer cell comes upon a virus, for example, it gloms onto it, then secretes proteins that riddle the germ like Swiss cheese, slaying it—mission accomplished—but at the same time sacrificing itself. Killers are most numerous at night, though they operate around the clock, as do their fellow T cells, the “helpers” and “suppressors,” which also perform crucial roles in our defense. (All three T cells take their T from the thymus, the butterfly-shaped gland located between the heart and breastbone, where they mature.) The other kind of lymphocyte, the B cells, which develop in the bone marrow, also emerge during deep sleep. And they, too, exist to make mincemeat of microbial bodies, but their methods are less direct. B cells produce preprogrammed weapons called antibodies, which head off into the blood to carry out their orders.
Our blood works not only to destroy the uninvited, but also to repair. In sleep, our circulatory system is infused with growth hormone, a product of the pineal gland and essential in helping rebuild damaged tissue. Growth hormone also rouses additional infection-fighting substances called cytokines, which, like a densely worded paragraph, can make us sleepy. It’s an extraordinary give-and-take. As sleep bolsters our immune system, our immune system bolsters sleep.
So, as it turns out, our moms were right all along.
Get back in bed this instant. Or, All you need is a good night’s sleep.
These refrains of countless generations of mothers are grounded not just in the clear messages our bodies send us but also in sound science. And while the mere mention of bed rest as a cure-all inevitably conjures up for me images from childhood, complete with the Vicks VapoRub and those spoonfuls of “grape-flavored” god-awfulness, the fact is, round-the-clock rest as a clinically proven treatment for sickness was first prescribed 150 years ago—the brainchild of a scientist from Paul and Hedwig Ehrlich’s hometown. Hermann Brehmer, a botanist from Silesia, contracted TB during the late 1840s and moved to the Himalayas to live out his final days. The young man’s prognosis was grim. TB, also called consumption, was almost never survivable and, as we now know, this bacterial infection has existed since prehistory; the royal mummies of ancient Egypt show clear evidence of its ravages. Between 1700 and 1900, according to historians, an estimated one billion people died of the disease. Hermann Brehmer did not expect to be an exception. To his great surprise, however, the fresh mountain air and abundant bed rest worked wonders, and he fully recovered. (What Brehmer’s unplanned regimen had done was deprive the bacteria of the conditions they needed to thrive, an immunologist today would explain, thus giving his immune system the edge it needed to fight back.) Following his return to Germany, Brehmer published in 1854 the banner-titled book Tuberculosis Is a Curable Disease, in which he espoused his TB “rest cure.” That same year he opened the world’s first tuberculosis sanatorium, the prototype for thousands built in Europe and the United States in the decades to follow. (By the 1940s these facilities had run their course, made obsolete by the widespread availability of antibiotics.) A mainstay of sanatoriums was the sleeping porch, where patients could rest, soak up sunshine, and “take the airs.” Of course, in true Michelin guide style, sanatoriums ran the full range of stars, from squalid public institutions to luxurious resorts for the well-to-do. In fact, when money was less o
f a concern, patients such as Paul Ehrlich could even make a vacation of their recovery, just as long as they made the commitment to follow doctor’s orders.
Now, one would think that Paul would’ve taken to forced rest like a cat to bathwater. Even Hedwig expected her thirty-four-year-old husband to go partway ’round the bend. In their five years together, she’d scarcely ever seen him take a day off. And yet, even before the Ehrlichs had reached their final destination of Egypt, the good doctor was showing early promise. The couple and their two daughters had first stopped over at a lakeside spa near Venice, and Hedwig, it was later reported, admitted her wonderment at how quickly Paul was adjusting to full-time R and R. “People always think I’m a hard worker,” he remarked at the time, “but they’re wrong. I can be as lazy as a giant snake.”
True enough. As Hedwig well knew, his favorite idle pastime had always been getting lost in books. So as not to disturb her sleep, he’d even divided their Berlin bedroom with a black curtain, which he’d draw and then read behind into the early morning. A perusal of his bookshelves would’ve revealed the breadth of his interests, from erudite leanings—including Greek classics and the latest works by contemporaries such as Friedrich Nietzsche, whose hymn-like verses Paul could recite by heart—to the other extreme, his great love, detective stories.